Heteroatom-containing tricyclic compounds

ABSTRACT

The invention concerns the compounds of formulae   &lt;IMAGE&gt; I  &lt;IMAGE&gt; II  and  &lt;IMAGE&gt; III  wherein the substituents have various significances. They can be prepared by various methods, e.g. acylation, reduction, alkylation, etc. They are indicated for use as pharmaceuticals, in particular as immunosuppressant, antiproliferative and antiinflammatory agents.

This is a continuation of application Ser. No. 08/058,50, filed May 6,1993 now abandoned.

The invention relates to the field of macrolides. It concerns thecompounds of formulae I to III ##STR2## wherein the symbol ₋₋ -- --represents a single bond or, when R₂ a is absent, a double bond;

R₁ represents an optionally protected hydroxy group and R_(1a)represents hydrogen;

or R₁ and R_(1a) together represent oxo;

R₂ represents an optionally protected hydroxy group or together with R₄forms the --OC(═O)O-- group, and R_(2a) represents hydrogen or isabsent;

whereby when the symbol ₋₋ -- -- is a single bond,

R₂ together with R_(2a) also represents oxo;

R₃ represents methyl, ethyl, n-propyl or allyl;

R₄ represents optionally protected hydroxy or together with R₂ forms the--OC(═O)O-- group, and R_(4a) represents hydrogen;

or R₄ together with R_(4a) represents oxo;

R₅ represents alkoxycarbonyloxy, halogen, optionally protected hydroxy,lower alkoxy, acyloxy or a group --OC(═X)N(R₁₀)R₁₁ ;

or R₅ together with R_(6a) forms a group --OC(═X)N(R'₁₀)-attached withthe nitrogen atom to the carbon atom carrying R_(6a), whereby Xrepresents oxygen or sulfur, R₁₀ and R₁₁ independently representhydrogen or lower alkyl or together with the nitrogen atom form a five-or six-membered ring optionally containing a second heteroatom such asnitrogen or oxygen, and R'₁₀ is hydrogen or lower alkyl;

or R₅ together with R_(8a) represents oxy, whereby R₈ representshydroxy;

R₆ represents hydroxy, and R_(6a) represents hydrogen or together withR₅ forms a group --OC(═X)N(R'₁₀)-as defined above;

or R₆ and R_(6a) together represent oxo;

R'₅ represents optionally protected hydroxy, lower alkoxy or acyloxy and

R'₆ represents hydroxy;

or R'₅ and R'₆ together form the --OC(═O)O-- group;

R"₅ represents hydroxy or lower alkoxy and R"₆ represents hydroxy;

or R"₅ and R"₆ together form the --OC(═O)O-- group;

R₇ represents methoxy or hydroxy;

R₈ represents an optionally protected hydroxy group, acyloxy,imidazolylcarbonyloxy or alkoxycarbonyloxy and R_(8a) representshydrogen;

or R₈ represents hydroxy and R_(8a) together with R₅ represents oxy;

or R₈ together with R_(8a) represents oxo; and

n represents 1 or 2;

in free form or salt form, hereinafter briefly named "the compounds ofthe invention".

R₁ and R₂ preferably are optionally protected hydroxy. R₃ preferably isethyl or allyl, especially ethyl. R₄ preferably is together with R_(4a)oxo. R₅ preferably is hydroxy or together with R_(8a) represents oxy.R'₅ and R"₅ preferably are hydroxy. R₈ preferably is hydroxy or oxo. R₆preferably is together with R_(6a) oxo. R₇ preferably is methoxy. Thesymbol ₋₋ -- -- preferably represents a single bond. n preferably is 2.X preferably is oxygen. R₁₀ and R₁₁ preferably are hydrogen or methyl ortogether with the nitrogen atom 1-imidazolyl, they especially aremethyl. R'₁₀ preferably is hydrogen or methyl.

Acyl and acyloxy preferably are alkylcarbonyl or, respectively,alkylcarbonyloxy of altogether 2 to 5 carbon atoms, preferablyacetyl(oxy), or formyl(oxy) or benzoyl(oxy). Halogen preferably ischlorine or bromine, it especially is chlorine. Lower alkyl and loweralkoxy preferably are of 1 to 4 carbon atoms, they especially are methyland, respectively, methoxy. Protected hydroxy preferably is hydroxyprotected by a conventional hydroxy-protecting group, it preferably ishydroxy protected by tert-butoxycarbonyl or trialkylsilyl, especiallytert-butyldimethylsilyl. Alkoxycarbonyloxy preferably is of altogether 2to 5 carbon atoms, it especially is methoxycarbonyloxy.

A compound of the invention in free form may be converted into a saltform where such forms exist, e.g. an acid addition salt form, inconventional manner and vice-versa.

A subgroup of compounds of the invention (compounds Ip₁) is thecompounds of formulae I to III as defined above, with the proviso that

R₂ and R₄ are other than together the --OC(═O)O-- group;

R₄ is other than protected hydroxy;

R₅ is other than alkoxycarbonyloxy, halogen, protected hydroxy, a group--OC(═X)N(R₁₀)R₁₁ as defined above or together with R_(6a) a group--OC(═X)N(R'₁₀)-- as defined above;

R'₅ is other than protected hydroxy; and

R₈ is other than protected hydroxy or alkoxycarbonyloxy of altogethermore than 2 carbon atoms.

A further subgroup of compounds of the invention (compounds Ip₂) is thecompounds of formulae I to III as defined above, with the proviso thatR₄, R₅ and R'₅ are other than protected hydroxy, and R₈ is other thanalkoxycarbonyloxy of altogether more than 2 carbon atoms.

A further group of compounds of the invention is the compounds offormulae Iq to IIIq ##STR3## wherein R_(1q) represents hydroxyoptionally protected by tert-butyldimethylsilyl or methylsulfonyl andR_(1aq) represents hydrogen; or R_(1q) and R_(1aq) together representoxo;

R_(2q) represents hydroxy optionally protected bytert-butyldimethylsilyl or together with R_(4q) forms the --OC(═O)O--group;

R_(3q) represents ethyl or allyl;

R_(4q) represents hydroxy optionally protected bytert-butyldimethylsilyl or together with R_(2q) forms the --OC(═O)O--group, and

R_(4aq) represents hydrogen;

or R_(4q) together with R_(4aq) represents oxo;

R_(5q) represents methoxycarbonyloxy; chlorine; hydroxy optionallyprotected by tert-butyldimethylsilyl, tert-butoxycarbonyl ormethylsulfonyl; methoxy; formyloxy, acetoxy or benzoyloxy; or a group--OC(═O)N(R_(10q))R_(11q) wherein

R_(10q) and R_(11q) independently represent hydrogen or methyl ortogether with the nitrogen atom form 4-morpholinyl;

or R_(5q) together with R_(6aq) forms a group --OC(═X)N(R'_(10q))--wherein X is as defined above and R'_(10q) is hydrogen or methyl;

or R_(5q) together with R_(8aq) represents oxy, whereby R_(8q)represents hydroxy;

R_(6q) represents hydroxy, and R_(6aq) represents hydrogen or togetherwith R_(5q) forms a group --OC(═X)N(R'_(10q))-- as defined above;

or R_(6q) and R_(6aq) together represent oxo;

R'_(5q) represents hydroxy optionally protected by benzoyl or acetyl andR'_(6q) represents hydroxy;

or R'_(5q) and R'_(6q) together form the --OC(═O)O-- group;

R"_(5q) represents hydroxy or methoxy and R"_(6q) represents hydroxy; orR"_(5q) and R"_(6q) together form the --OC(═O)O-- group; and

R_(8q) represents hydroxy optionally protected bytert-butyldimethylsilyl or methylsulfonyl; acetoxy or benzoyloxy; or1-imidazolylcarbonyloxy; and

R_(8aq) represents hydrogen;

or R_(8q) represents hydroxy and R_(8aq) together with R_(5q) representsoxy;

or R_(8q) together with R_(8a) q represent oxo;

in free form or salt form.

The preferred stereochemical configuration of the compounds of formulaeIq to IIIq is as indicated below for formulae Is to Vs.

The invention also provides a process for the preparation of thecompounds of formulae I to III, which comprises

a) for the production of compounds of formulae ##STR4## wherein thesubstituents are as defined above, reacting a compound of formula IV##STR5## wherein the substituents are as defined above, with anappropriate base or organic or inorganic salt, optionally in thepresence of a phase transfer catalyst, or

b) for the production of compounds of formula Ia or IIa, reacting acompound of formula V ##STR6## wherein R₉ represents alkyl and the othersubstituents are as defined above, with an appropriate base or organicor inorganic salt, optionally in the presence of a phase transfercatalyst, or

c) for the production of compounds of formulae I to III wherein R₂ andR₄, and/or R'₅ and R'₆ respectively R"₅ and R"₆ together form the--OC(═O)O-- group, reacting a compound of formula I, II or III whereinR₂ and R₄, and/or R'₅ and R'₆ respectively R"₅ and R"₆ representhydroxy, with phosgene, diphosgene or triphosgene in the presence of anacid binder, or

d) for the production of compounds of formulae I to III wherein at leastone of the substituents R₁, R₂, R₄, R₆ or R₈ represents hydroxy,appropriately reducing a compound of formula I, II or III wherein atleast one of the substituents R₁, R₂, R₄, R₆ or R₈ together with R_(1a),R_(2a), R₆ a or, respectively, R_(8a) represents oxo, or

e) for the production of compounds of formulae I to III wherein R₅, R'₅and R"₅ represent lower alkoxy, appropriately alkylating a compound offormula I, II or III wherein R₅, R"₅ and R'₅ represent hydroxy, or

f) for the production of compounds of formula I or II wherein at leastone of the substituents R₅, R'₅ or R₈ represents acyloxy,alkoxycarbonyloxy or --OC(═X)N(R₁₀)R₁₁, appropriately acylating acompound of formula I or II wherein at least one of the substituents R₅,R'₅ or R₈ represents hydroxy, where indicated followed by the additionof NH₃ or of an appropriate amine, or

g) for the production of compounds of formula I wherein R₈ together withR_(8a) represents oxo, appropriately oxidizing a compound of formula Iwherein R₈ represents hydroxy and R_(8a) represents hydrogen, or

h) for the production of compounds of formula I wherein R₅ representshalogen, appropriately halogenating a compound of formula I wherein R₅represents hydroxy, and/or optionally deprotecting the resultantcompounds of formulae I to III wherein a protected hydroxy group(s) is(are) present, and/or optionally protecting the resultant compounds offormulae I to III wherein a free hydroxy group(s) is (are) present,

and recovering the resultant compounds in free form or salt form.

The process of the invention can be carried out in conventional manner.

In process variant a) and b) the reaction preferably is effected in aninert solvent, such as an ether, e.g. tetrahydrofuran, dioxane ordiethylether, an aromatic hydrocarbon, e.g. benzene or toluene, analcohol, e.g. methanol or ethanol, dimethylsulfoxide or acetonitrile.The bases or metallic salts are preferably CsF, Cs₂ CO₃. K₂ CO₃, LiOH,NaOH, KOH, Mg(OR)₂, whereby R represents a lower alkyl group, KH, NaH, atertiary amine, e.g. triethylamine, or an amidine, e.g. 1,8-diazabicyclo5.4.0!-undec-7-ene (DBU). As phase transfer catalyst quaternatedammonium salts or preferably crown ethers, e.g. crown 18.6!, may beused. The reaction is preferably carried out at a temperature betweenabout -30° and about 50° C., especially at about room temperature.Depending on the reaction conditions used (reactants, temperature,reaction time, etc.), specific regio- and/or diastereoisomeric forms ofthe compounds of formula Ia, IIa or IIIa or mixtures thereof areobtained.

In process variant b) the configuration in position 9 is determined bythe configuration at position 9 in the starting material of formula V.Reaction mixtures may be worked up in conventional manner, e.g.chromatographically.

Process variant c) for the production of the carbonates is carried outpreferably in an inert solvent such as an ether, e.g. tetrahydrofuran,diethylether or dioxane, a chlorinated hydrocarbon, e.g.1,2-dichloroethane or methylene chloride, or acetonintrile, attemperatures between about -20° C. and the boiling temperature of thereaction mixture, preferably at about room temperature. A tertiary aminecan be used as acid binder, e.g. triethylamine, 4-dimethylaminopyridineor pyridine.

The reduction, process variant d), can be effected in conventionalmanner. The reducing agent conveniently is a hydride-reagent, e.g.NaBH₄, diisobutyl aluminiumhydride or tetramethylammonium triacetoxyborohydride. The process may be carried out in an inert solvent such asan ether or cyclic ether, e.g. tetrahydrofuran, dioxane or diethylether,an aromatic hydrocarbon, e.g. toluene, or in the case oftetramethylammonium triacetoxy borohydride as reducing agent, also inacetonitrile and/or acetic acid, at temperatures preferably betweenabout -70° and about 50° C., especially at about room temperature.

Process variant e) is an alkylation. It preferably is carried out in anon-protic solvent, e.g. in an ether, a cyclic ether, an aromatichydrocarbon, dimethyl formamide or dimethyl sulfoxide, in the presenceof a base such as a non-nucleophilic nitrogen base, e.g. DBU, or analkali hydride, e.g. sodium or potassium hydride, or a metallic salt,e.g. a carbonate or fluoride of potassium, sodium or cesium, optionallyin the presence of a crown ether. The alkylating agent preferably is ahalogenide, tosylate or mesylate, e.g. alkyl iodide, especially methyliodide. The reaction is carried out at room temperature or elevatedtemperature, preferably at room temperature.

Acylation according to process variant f) can be carried out inconventional manner, e.g. in an inert solvent such as acetonitrile ordichloromethane, e.g. with an acid chloride or an acid anhydride in thepresence of an acid binder such as 4-dimethylaminopyridine or with anacid in the presence of an acid binder such as 4-dimethylaminopyridineor with an acid in the presence of a carbodiimide such asdicyclohexylcarbodiimide. The acylation may be carried out withdiphosgene or thiophosgene followed by the addition of NH₃ or of anappropriate amine to give the corresponding carbamates wherein R₅represents a group of formula --OC(═X)N(R₁₀)R₁₁ as defined above. Whenthe reaction is carried out in the presence of NH₃ or a primary amine,the end products wherein R₆ and R_(6a) together represent oxo mayundergo a cyclisation and form compounds of formula ##STR7## wherein thesubstituents are as defined above and which also form part of theinvention.

Process variant g) is an oxidation. It may be carried out inconventional manner, e.g. in an inert solvent such as an aromatichydrocarbon, e.g toluene, or a halogenated hydrocarbon, e.g.dichloromethane or dichloroethane, at temperatures between about 0° C.and room temperature, preferably at about room temperature. The reactionis effected e.g. with N-methyl-morpholine-N-oxide in the presence of acatalytic amount of tetrapropylammonium perruthenate, or with1,1,1-tris(acetoxy)-1,1-dihydrobenziodoxol-3(1H)one (Dess-Martinmethod). The oxidized end compounds of formula I wherein R₈ togetherwith R_(8a) represents oxo and R₅ represents hydroxy, may exist inequilibrium with corresponding compounds of formula I wherein R₈represents hydroxy and R₅ together with R_(8a) represents oxy, i.e. withcompounds of formula Ic ##STR8## wherein the substituents are as definedabove and which also form part of the invention. Process variant g)gives mixtures of these compounds which may be separated in conventionalmanner, e.g. chromatographically. Depending on the starting material andthe reaction conditions employed, especially on the oxydizing reagent,the oxydation may take place in the positions 10, 14, 22, 24 and/or 33.Different reaction ability and/or selective protection of hydroxy groupsmay yield final products which are oxydized only in selected positions.

Process variant h) may be carried out in for halogenation conventionalmanner, e.g. by reacting with a halogenating agent such as thionylchloride in an appropriate solvent, e.g. in pyridine or tetrahydrofuran,at temperatures e.g. between about 0° C. and room temperature,preferably at about room temperature.

The process variants of the invention may be carried out simultaneously,especially process variant e) may be effected in a "one pot reaction"with process variants a) or b). Mixtures of end products may beseparated in conventional manner, e.g. chromatographically.

Compounds of formula Ia may be in equilibrium with compounds of formulaIIa. In many cases these tautomeric forms may be isolated.

Process variants a) and b) signify generally

a) when reacting a compound of formula IV to obtain compounds offormulae Ia and IIa: rearrangement and cyclisation;

b) when reacting a compound of formula IV to obtain compounds of formulaIIIa: cyclisation;

c) when reacting a compound of formula V to obtain compounds of formulaeIa and IIa: cyclisation.

When compounds obtained according to process variants a) to h) have oneor more protected hydroxy group(s), the protecting group(s) may beremoved in conventional manner to give the corresponding unprotectedcompounds. The removal of e.g. tert-butyldimethylsilyl ortert-butoxycarbonyl may be effected by treatment with hydrofluoric acidin a solvent such as acetonitrile. Depending on the reaction conditionschosen (e.g. duration or temperature) the removal can be steered in sucha manner that either all or only some protecting groups are eliminated.

When compounds obtained according to process variants a) to h) have oneor more free hydroxy group(s), the hydroxy group(s) may be protected inconventional manner to give the corresponding protected compounds.Depending on the reaction conditions chosen the reaction can be steeredin such a manner that either all or only some hydroxy groups areprotected. Suitable protecting groups are conventional hydroxyprotecting groups such as tert-butoxycarbonyl or trialkylsilyl,preferably tert-butyldimethylsilyl.

Partial deprotection or protection is particularly indicated where adefinite hydroxy group is to be reacted in a subsequent reaction step.

The compounds of formulae I to V have a number of chiral centers and mayexist in a variety of stereoisomers. The process variants of theinvention result normally in a mixture of such isomers. Depending on theconditions and the type of reaction the process can be steered in suchmanner that a specific isomer preferably is produced. The inventionprovides all optical and geometric isomers as well as racemic mixtures.The isomers may be resolved or separated by conventional techniques.However the preferred stereochemistry at various chiral carbon atoms isshown in formulae Is to Vs: ##STR9##

In the above formulae Is to Vs

when R₁ is other than oxo together with R_(1a), then R₁ preferably isbound with the α-configuration to the carbon atom in 33 position;

R₃ preferably is bound with the α-configuration to the carbon atom in 21position;

when R₄ is other than oxo together with R_(4a), then R₄ preferably isbound with the α-configuration to the carbon atom in 22 position;

A compound of the invention may be isolated and purified from thereaction mixture in conventional manner.

The starting material of formula V, preferably in form of thediastereoisomers hereinafter designated diastereoisomers C, may beobtained by reacting a compound of formula IV analogously to processvariant a) followed by reaction of the resultant product with adiazoalkane. The first step of this process may be carried out asdescribed above, e.g. with KOH/crown ether in tetrahydrofuran. Thereaction product is worked up in conventional manner, the residueredissolved in an inert solvent, e.g. dichloromethane, and trituratedwith a solution of a diazoalkane, preferably diazomethane ordiazoethane, in an inert solvent, e.g. ether. The resultant reactionmixture may be worked up in conventional manner.

The starting material of formula V, preferably in form of thediastereoisomers hereinafter designated diastereoisomers A, may beobtained by reacting a compound of formula IV with a base, followed byreaction of the resultant product with a diazoalkane. This process stepmay be carried out in conventional manner. It preferably is effected ina mixture of solvents, e.g. in a mixture of tetrahydrofuran and water,using LiOH or Ca(OH)₂ as base. The reaction product is worked up inconventional manner, the residue redissolved in an inert solvent, e.g.dichloromethane, and titurated with a solution of a diazoalkane,preferably diazomethane or diazoethane, in an inert solvent, e.g. ether.The resultant reaction mixture may be worked up in conventional manner.

Insofar as their preparation is not specifically described herein, e.g.in the Examples, the compounds used as starting materials are known orcan be obtained in conventional manner from known compounds, e.g.starting from appropriate Streptomyces strains such as Streptomycestsukubaensis No. 9993 described in e.g. Fujisawa EP 184162. Samples canbe obtained from the Fermentation Research Institute, Tsukuba, Ibaraki305, Japan under provisions of the Budapest Treaty under deposit No.FERM BP-927. This strain has been redeposited on Apr. 27, 1989 with theAgricultural Research Culture Collection International Depository,Peoria, Ill. 61604, USA under the provisions of the Budapest Treatyunder deposit No. NRRL 18488.

The following Examples illustrate the invention. They are notlimitative. All temperatures are in degrees Centigrade. In the NMRspectra all chemical shift values are in ppm; samples are measured inCDCl₃ unless indicated otherwise. The following abbreviations are used:

O-tBDMS=tert-butyldimethylsilyloxy

db=double bond

sb=single bond

Im=1-imidazolylcarbonyl

Bz=benzoyl

DBU=1,8-diazabicyclo 5.4.0!undec-7-ene

Ac=acetyl

BOC=tert-butoxycarbonyl ##STR10##

EXAMPLE 1

R₁ =R₂ =O-tBDMS; R₃ =C₂ H₅ ; R_(4a) =O; R₇ =OCH₃ ; ₋₋ -- -- =sb; n=2;R_(1a) =R_(2a) =H (process a)

1a: compound of formula IIIa

1b: compound of formula IIa (diastereoisomer A)

1c: compound of formula Ia (diastereoisomer A)

1d: compound of formula Ia (diastereoisomer B)

1e: compound of formula Ia (diastereoisomer C)

4 g of crown 18.6!ether and 12.7 g of cesium carbonate (or 5 g of cesiumfluoride) are added to a solution of 20 g 24,33-bis-O-tBDMS-FR 520 in250 ml of dry tetrahydrofuran. The reaction mixture is stirred for 3hours at room temperature, then partitioned between ethyl acetate and 1Nhydrochloric acid, the phases are separated, the organic phase is washedwith brine, dried over sodium sulfate, filtered and evaporated undervacuum. Chromatography of the residue (n-hexane/ethyl acetate=3/1→1/2)gives the title substances as colourless foams.

EXAMPLE 2

R₁ =R₂ =O-tBDMS; R₃ =C₂ H₅ ; R₄ +R_(4a) =O; R₇ =OCH₃ ; ₋₋ -- -- =sb;n=2; R_(1a) =R_(2a) =H; diastereoisomers A (process b)

2a: compound of formula IIa

2b: compound of formula Ia

1 ml of diazabicycloundecene is added to a solution of 5.2 g of thecompound of formula V (R₁ =R₂ =O-tBDMS; R_(1a) =R_(2a) =H; R₃ =C₂ H₅ ;R₄ +R_(4a) =O; R₇ =OCH₃ ; R₉ =CH₃ ; n=2; ₋₋ -- -- =sb; diastereoisomerA) in 250 ml of acetonitrile. The reaction mixture is stirred for 70minutes at room temperature and then worked up as described in example 1(n-hexane/ethyl acetate=3/2) to give the title substances as colourlessfoams.

Analogously as described in examples 1 and 2 the following compounds offormulae Ia, IIa and IIIa are obtained in form of colourless foams (R₇=OCH₃ ; n=2; ₋₋ -- -- =sb; R_(1a) =R_(2a) =H):

    __________________________________________________________________________    ex:       form.           isomer               R.sub.1  R.sub.2                               R.sub.4                                 R.sub.4a                                    R.sub.3  starting material:    __________________________________________________________________________    3a IIIa           --  --O--tBDMS                        --O--tBDMS                               O    --CH.sub.2 CH═CH.sub.2                                             24,33-di--O--tBDMS--                                             FK 506    3b IIa A   --O--tBDMS                        --O--tBDMS                               O    --CH.sub.2 CH═CH.sub.2    3c Ia  A   --O--tBDMS                        --O--tBDMS                               O    --CH.sub.2 CH═CH.sub.2    3d Ia  C   --O--tBDMS                        --O--tBDMS                               O    --CH.sub.2 CH═CH.sub.2    4  IIIa           --  --O--SO.sub.2 --CH.sub.3                        --O--tBDMS                               O    --C.sub.2 H.sub.5                                             Compound A)    5  IIIa           --  --O--SO.sub.2 --CH.sub.3                        --O--tBDMS                               O    --CH.sub.2 CH═CH.sub.2                                             Compound B)    6a IIIa           --  --OH     --OH   O    --C.sub.2 H.sub.5                                             FR 520    6b IIa A   --OH     --OH   O    --C.sub.2 H.sub.5    6c Ia  A   --OH     --OH   O    --C.sub.2 H.sub.5    6d Ia  B   --OH     --OH   O    --C.sub.2 H.sub.5    6e Ia  C   --OH     --OH   O    --C.sub.2 H.sub.5    6f Ia  D   --OH     --OH   O    --C.sub.2 H.sub.5    7a IIIa           --  --OH     --OH   O    --CH.sub.2 CH═CH.sub.2                                             FK 506    7b IIa A   --OH     --OH   O    --CH.sub.2 CH═CH.sub.2    7c Ia  A   --OH     --OH   O    --CH.sub.2 CH═CH.sub.2    7d Ia  B   --OH     --OH   O    --CH.sub.2 CH═CH.sub.2    7e Ia  C   --OH     --OH   O    --CH.sub.2 CH═CH.sub.2    8  Ia  A   --O--tBDMS                        --OH   O    --C.sub.2 H.sub.5                                             33-O--tBDMS-FR520 a)    9a IIIa           --  --O--tBDMS                        --O--CO--O--                                 H  --C.sub.2 H.sub.5                                             Compound G)    9b Ia  A   --O--tBDMS                        --O--CO--O--                                 H  --C.sub.2 H.sub.5    9c Ia  C   --O--tBDMS                        --O--CO-O--                                 H  --C.sub.2 H.sub.5    10 Ia  C   --O--tBDMS                        --O--tBDMS                               O    --C.sub.2 H.sub.5                                             Compound C)    11 Ia  C   --O--tBDMS                        --O--tBDMS                               O    --CH.sub.2 CH═CH.sub.2                                             Compound D)    12a       Ia  A   --O--tBDMS                        --O--tBDMS                               O    --CH.sub.2 CH═CH.sub.2                                             Compound F)    12b       IIa A   --O--tBDMS                        --O--tBDMS                               O    --CH.sub.2 CH═CH.sub.2    __________________________________________________________________________     a) Deprotection or, respectively, reduction of this compound gives the     compound of Example 6c (= Example 73) or, respectively, of Example 28

EXAMPLE 13

Compound of formula III (R₁ =R₂ =O-tBDMS; R₃ =C₂ H₅ ; R₄ +R_(4a) =O; R"₅+R"₆ =OCO--O; R₇ =OCH₃ ; ₋₋₋₋₋₋ =sb; n=2; R_(1a) =R_(2a) =H (process c)

To a solution of 0.8 g of the compound of formula III (R₁ =R₂ =O-tBDMS;R₃ =C₂ H₅ ; R₄ +R_(4a) =O; R"₅ =R"₆ =OH; R₇ =OCH₃ ; ₋₋ -- -- =sb; n=2;R_(1a) =R_(2a) =H) in 40 ml of acetonitrile are added in turn 0.2 ml ofdiphosgene and 1.75 g of dimethylaminopyridine. The reaction mixture isstirred for 1.5 hours at room temperature and then worked up asdescribed in example 1 (n-hexane/ethyl acetate=9/1) to give the titlesubstance in form of a colourless foam.

Analogously as described in example 13 the following compounds offormulae I to III are obtained in form of colourless foams (R₃ =C₂ H₅ ;R₇ =OCH₃ ; ₋₋ -- -- =sb; n=2; R_(1a) =R_(2a) =R_(4a) =R_(8a) =H):

    __________________________________________________________________________                                   R.sub.5                                         R.sub.6                                   R'.sub.5                                         R'.sub.6                                               starting    ex:      form.          isomer              R.sub.1                     R.sub.2                            R.sub.4                                   R".sub.5                                         R".sub.6                                            R.sub.8                                               material:    __________________________________________________________________________    14      II  A   --O--tBDMS                     --O--tBDMS                            --O--tBDMS                                   --O--CO--O--                                            -- Ex. 1b    15      I   A   --O--tBDMS                     --O--CO--O--  OH    O* OH Ex. 28    16      I   C   --OH   --O--CO--O--  --O--BOC                                         O* OH Ex. 27    17      III --  --OH   --O--CO--O--  --O--CO--O--                                            -- Ex. 25    18      I   B   --OH   --O--CO--O--  OH    O* OH  Ex. 26a    __________________________________________________________________________     *together with R.sub.6a

EXAMPLE 19

Compound of formula I (R₁ =R₂ =O-tBDMS; R₃ =C₂ H₅ ; R₄ +R_(4a) =O; R₅=R₆ =R₈ =OH; R₇ =OCH₃ ; ₋₋ -- -- =sb; n=2; R_(1a) =R_(2a) =R_(6a)=R_(8a) =H; diastereoisomer C) (process d)

0.5 g of tetramethylammonium triacetoxy boronhydride are added to asolution of 1 g of the compound of formula I (R₁ =R₂ =O-tBDMS; R₃ =C₂ H₅; R_(1a) =R_(2a) =R_(8a) =H; R₄ +R_(4a) =R₆ +R_(6a) =O; R₅ =R₈ =OH; R₇=OCH₃ ; ₋₋ -- -- =sb; diastereoisomer C) in 30 ml of acetonitrile and 5ml of acetic acid. The reaction mixture is stirred for 3.5 hours at roomtemperature and then partitioned between saturated aqueous NaHCO₃-solution and ethyl acetate. The organic phase is separted, washed inturn with brine, 1N hydrochloric acid and brine again, dried over Na₂SO₄, filtered and evaporated under vacuum. Chromatography of the residue(ethyl acetate) gives the title substance in form of a colourless foam.

Analogously as described in example 19 the following compounds offormulae I, II and III are obtained in form of colourless foams (R₃ =C₂H₅ ; R₇ =OCH₃ ; R₈ =OH; R_(1a) =R_(2a) =H; ₋₋ -- -- =sb; n=2):

    __________________________________________________________________________                                    R.sub.5                                         R.sub.6                                    R'.sub.5                                         R'.sub.6                                                 starting    ex:       form.           isomer                R.sub.1                       R.sub.2                              R.sub.4                                 R.sub.4a                                    R".sub.5                                         R".sub.6                                            R.sub.6a                                                 material    __________________________________________________________________________    20 I   B    --O--tBDMS                       --O--tBDMS                              O     OH   OH H    Ex. 1d    21 I   A    --O--tBDMS                       --O--tBDMS                              O     OH   OH H    Ex. 1c    22 II  A    --O--tBDMS                       --O--tBDMS                              OH H  OH   OH --   Ex. 1b     23a        I   A/cis                 OH     --O--CO--O--                                  H  OH   OH                                             H                                                 Ex. 112    23b       I   A/trans                OH     --O--CO--O--                                 H  OH   OH H     24a        I   C    --O--tBDMS                        --O--tBDMS                               OH                                  H  OH   O                                                 Ex. 1e.sup.a)    24b       I   C    --O--tBDMS                       --O--tBDMS                              OH H  OH   OH H    25 III --   --O--tBDMs                       --O--tBDMS                              OH H  --O--CO--O--                                            --   Ex. 100     26a        I   B    OH     OH     OH                                  H  OH   O                                                 Ex. 6d    26b       I   B    OH     OH     OH H  OH   OH H    27 I   C    OH     OH     OH H  O--BOC                                         O       Ex. 115    28 I   A    --O--tBDMS                       OH     OH H  OH   O       Ex. 8    __________________________________________________________________________     a) Deprotection gives the compound of Example 118

EXAMPLE 29

Compound of formula I (R₁ =R₂ =O-tBDMS; R₃ =C₂ H₅ ; R₄ +R_(4a) =R₆+R_(6a) =O; R₅ =R₇ =OCH₃ ; R₈ =OH; ₋₋ -- -- =sb; n=2; R_(1a) =R_(2a)=R_(8a) =H) (process d)

200 mg of crown 18.6!ether, 200 mg of cesium carbonate and 1.5 ml ofmethyl iodide are added to a solution of 100 mg of the compound offormula I (R₁ =R₂ =O-tBDMS; R₃ =C₂ H₅ ; R_(1a) =R_(2a) =R_(8a) =H; R₄+R_(4a) =R₆ +R_(6a) =O; R₅ =R₈ =OH; R₇ =OCH₃ ; ₋₋ -- -- =sb; n=2;diastereoisomer A) and stirred for 1.5 hours at room temperature. Thereaction mixture is worked up as described in example 1 (n-hexane/ethylacetate=2/1) to give the title substance in form of a colourless foam.

Analogously as described in example 29 the following compounds offormula I and III are obtained in form of colourless foams (R₃ =C₂ H₅ ;R_(1a) =R_(2a) =R_(8a) =H; R₄ +R_(4a) =O; R₇ =OCH₃ ; R₈ =OH; ₋₋ -- --=sb; n=2):

    __________________________________________________________________________                                 R".sub.6                                       starting    ex:      form.          isomer              R.sub.1                     R.sub.2                            R.sub.5                                 R.sub.6                                    R.sub.6a                                       material    __________________________________________________________________________    30      III --  --O--tBDMS                     --O--tBDMS                            --OCH.sub.3                                 OH -- Ex. 1a    31      I   C   --O--tBDMS                     --O--tBDMS                            --OCH.sub.3                                 O     Ex. 1e    __________________________________________________________________________

EXAMPLE 32

R₁ =R₂ =O-tDMS; R₃ =C₂ H₅ ; R₄ +R_(4a) =O; R₇ =OCH₃ ; -- -- --=sb; n=2;R_(1a) =R_(2a) =H; diastereoisomer A (process f)

32a: compound of formula I (R₅ =OH; R₆ +R_(6a) =O; R₈ =O-Bz; R_(8a) =H)

32b: compound of formula I (R₅ =O-Bz; R₆ +R_(6a) =O; R₈ =O-Bz; R_(8a)=H)

32c: compound of formula I (R₅ =O-Bz; R₆ +R_(6a) =O; R₈ =OH; R_(8a) =H)

32d: compound of formula II: (R'₅ =O-Bz; R'₆ =OH)

5 mol equivalents of 4-dimethylaminopyridine and 1.3 mol equivalents ofbenzoyl chloride are added to a solution of 0.6 g of the compound offormula I (R₁ =R₂ =O-tBDMS; R₃ =C₂ H₅ ; R_(1a) =R_(2a) =R_(8a) =H; R₄+R_(4a) =R₆ +R_(6a) =O; R₅ =R₈ =OH; R₇ =OCH₃ ; diastereoisomer A) or ofthe compound of formula II (R₁ =R₂ =O-tBDMS; R₃ =C₂ H₅ ; R_(1a) =R_(2a)=H; R₄ +R_(4a) =O; R'₅ =OH; R'₆ =OH; R₇ =OCH₃ ; ₋₋ -- -- =sb; n=2). Thereaction mixture is stirred for 45 minutes and then worked up asdescribed in example 1 (n-hexane/ethyl acetate=4/1→2/1) to yield thetitle substances in form of colourless foams.

Analogously as described in example 32 the following compounds offormula I and II are obtained in form of colourless foams (R₁ =R₂=O-tBDMS; R₃ =C₂ H₅ ; R_(1a) =R_(2a) =H; R₄ +R_(4a) =O; R₇ =OCH₃ ; ₋₋ ---- =sb; n=2):

    __________________________________________________________________________                       R.sub.6            starting    ex:       form.           isomer               R.sub.5 R'.sub.6                          R.sub.6a                             R.sub.8 R.sub.8a                                          material    __________________________________________________________________________    33 I   A   OH      O     O--Im   H    Ex. 1b or 1c    34 I   C   O--Ac   O     O--Ac   H    Ex. 1e     35a        I   C   O--Bz   O     O--Bz   H                                          Ex. 1e    35b       I   C   O--Bz   O     OH      H     36a        I   C   --O--SO.sub.2 CH.sub.3                        O     --O--SO.sub.2 CH.sub.3                                      H                                          Ex. 1e    36b       I   C   OH      O     --O--SO.sub.2 CH.sub.3                                     H    37a       I   A   O--Ac   O     O--Ac   H    37b       I   A   OH      O     O--Ac   H    37c       I   A   O--Ac   O     OH      H    Ex. 1b or 1c    37d       II  A   O--Ac   OH -- --      --    38 I   A   --O--CHO                       O     O            Ex. 50    39 I   A   --O--COOCH.sub.3                       O     --OtBDMS                                     H    Ex. 58b    40 I   A   --O--CHO                       O     --OtBDMS                                     H    Ex. 58b a)    41 I   B   --O--CHO                       O     --OtBDMS                                     H    Ex. 60a    42 I   C   --O--CHO                       O     --OtBDMS                                     H    Ex. 59    43 I   C   --O--BOC                       O     --OtBDMS                                     H    Ex. 59    __________________________________________________________________________     a) Deprotection gives the compound of Example 6c (= Example 73)

EXAMPLE 44

Compound of formula I (R₁ =R₂ =R₈ =0-tBDMS; R₃ =C₂ H₅ ; R₄ +R_(4a) =R₆+R_(6a) =O; R₅ =O--CO--(4-morpholinyl); R₇ =OCH₃ ; ₋₋₋₋₋₋ =sb; n=2;R_(1a) =R_(2a) =R_(8a) =H; diastereoisomer A) (process f)

10 equ. of 4-dimethylaminopyridine and 1 molequ. of diphosgene are addedto a solution of 2 g of the compound of formula I (R₁ =R₂ =R₈ =O-tBDMS;R₃ C₂ H₅ ; R_(1a) =R_(2a) =R_(8a) =H; R₄ +R_(4a) =R₆ +R_(6a) =O; R₅ =OH;R₇ =OCH₃ ; ₋₋ -- -- =sb; n=2; diastereoisomer A) in 50 ml ofacetonitrile, the reaction mixture is stirred for 20 minutes at roomtemperature, then poured onto 500 ml of ethyl acetate and 20 ml ofmorpholine, rigorously stirred for 10 minutes and then worked up asdescribed in example 1 (n-hexane/ethyl acetate=7/1) to yield thesubstance as a colourless foam.

Analogously as described in example 44 the following compounds offormula I and Ib are obtained in form of colourless foams (R₁ =R₂O-tBDMS; R₃ =C₂ H₅ ; R₄ +R_(4a) =O; R₇ =OCH₃ ; ₋₋ -- -- =sb; n=2; R₆=OH; R_(1a) =R_(2a) =R_(6a) =H):

    __________________________________________________________________________    ex.       form.           isomer               R.sub.5    R.sub.8                                 R.sub.8a                                      starting material    __________________________________________________________________________    45 I   A   --O--CO--NH.sub.2                          --O--tBDMS                                 H    Ex. 58b    46 I   A   --O--CO--N(CH.sub.3).sub.2                          --O--tBDMS                                 H    Ex. 58b     47a        Ib  C    --        O                                      (R'.sub.10 = H, X = O)                                                   Ex. 51    47b       I   C    --O--CO--NH.sub.2                          O     48        Ib  A   --         --O--tBDMS                                  H    (R'.sub.10 = CH.sub.3, X = O)                                                   Ex. 58b    49 Ib  A   --         --O--tBDMS                                 H    (R'.sub.10 = CH.sub.3, X    __________________________________________________________________________                                      = S)

EXAMPLE 50 Compound of formula I (R₁ =R₂ =O-tBDMS; R₃ =C₂ H₅ ; R₄+R_(4a) =R₆ +R_(6a) =R₈ +R_(8a) =O; R₅ =OH; R₇ =OCH₃ ; ₋₋₋₋₋₋ =sb; n=2;R_(1a) =R_(2a) =H; diastereoisomer A) (process g)

0.5 g of 1,1,1-tris(acetoxy)-1,1-dihydro-benziodoxol-3(1H)-one are addedto a solution of 0.5 g of the compound of formula I (R₁ =R₂ =O-tBDMS; R₃=C₂ H₅ ; R₄ +R_(4a) =R_(6a) =O; R₅ =R₈ =OH; R₇ =OCH₃ ; ₋₋ -- -- =sb;n=2; R_(1a) =R_(2a) =R_(8a) =H; diastereoisomer A) in 50 ml of methylenechloride. The reaction mixture is stirred for 3 hours at roomtemperature, then filtered over silicagel, washed with n-hexane/ethylacetate (1/1) and the filtrate evaporated under vacuum. Chromatographyof the residue (n-hexane/ethyl acetate=3/1) gives the title substance inform of a colourless foam.

Analogously as described in example 50 the following compounds offormula I are obtained in form of colourless foams (R₃ =C₂ H₅ ; R₄+R_(4a) =R₆ +R_(6a) =R₈ +R_(8a) =O; R₇ =OCH₃ ; ₋₋ -- -- =sb; n=2; R_(2a)=H):

    ______________________________________        iso-                                  starting    ex. mer    R.sub.1    R.sub.1a                               R.sub.2  R.sub.5                                              material    ______________________________________    51  C      --O--tBDMS H    --O--tBDMS                                        OH    Ex. 1e    52  A      O               --O--tBDMS                                        OH    Ex. 70    53  A      --O--tBDMS H    --O--tBDMS                                        OCH.sub.3                                              Ex. 29    54  C      --O--tBDMS H    --O--tBDMS                                        OCH.sub.3                                              Ex. 31    ______________________________________

EXAMPLE 55

Compound of formula I (R₁ =R₂ =R₈ =O-tBDMS; R₃ =C₂ H₅ ; R₄ +R_(4a) =R₆+R_(6a) =O; R₅ =Cl; R₇ =OCH₃ ; ₋₋ -- -- =sb; n=2; R_(1a) =R_(2a) =R_(8a)=H; diastereoisomer epi-A) (process h)

0.3 ml of thionyl chloride in 5 ml of pyridine are added to a solutionof 1 g of the compound of formula I (R₁ =R₂ =O-tBDMS; R₃ =C₂ H₅ ; R₄+R_(4a) =R₆ +R_(6a) =O; R₅ =OH; R₇ =OCH₃ ; R₈ =O-t-BDMS; R_(1a) =R_(2a)=R_(8a) =H; ₋₋ -- -- =sb; n=2; diastereoisomer A) in 100 ml oftetrahydrofuran, the reaction mixture is stirred at room temperature for15 hours and then partitioned between ethyl acetate and a saturatedaqueous solution of sodium bicarbonate. The organic phase is separated,washed twice with 1N HCl and water, dried over Na₂ SO₄ and the solventsare removed under vacuo. Column chromatography (n-hexane/ethylacetate=9/1) gives the title compound as a colourless foam.

Analogously as described in example 55 the following compounds offormula I are obtained in form of colourless foams (R₃ =C₂ H₅ ; R₄+R_(4a) =R₆ +R_(6a) =O; R₇ =OCH₃ ; R₈ =O-tBDMS; R_(1a) =R_(2a) =R_(8a)=H; ₋₋ -- -- =sb; n=2):

    ______________________________________    ex: isomer  R.sub.1    R.sub.2  R.sub.5                                        starting material    ______________________________________    56  epi-C   --O--tBDMS --O--tBDMS                                    Cl  Ex. 59    57  epi-B   --O--tBDMS --O--tBDMS                                    Cl  Ex. 60a    ______________________________________

EXAMPLE 58

Compound of formula I (R₁ =R₂ =R₈ =O-tBDMS; R₃ =C₂ H₅ ; R₄ +R_(4a) =R₆+R_(6a) =O; R₇ =OCH₃ ; ₋₋₋₋₋₋ =sb; n=2; R_(1a) =R_(2a) =R_(8a) =H;diastereoisomer A) (protection)

a) R₅ =O-tBDMS

b) R₅ =OH

5 equ. of 2,6-lutidine and 2 equ. of t.butyldimethylsilyl triflate areadded to a solution of the compound of formula I (R₁ =R₂ =O-tBDMS; R₃=C₂ H₅ ; R₄ +R_(4a) =R₆ +R_(6a) =O; R₅ =R₈ =OH; R₇ =OCH₃ ; R_(1a)=R_(2a) =R_(8a) =H; ₋₋ -- -- =sb; n=2; diastereoisomer A) in 50 ml ofacetonitrile, the reaction mixture is stirred for 1.5 hours at roomtemperature and then worked up as described in example 1. Chromatography(eluent=toluene) gives the title compounds as colourless foams.

Analogously as described in example 58 the following compounds offormula I are obtained in form of colourless foams (R₁ =R₂ =R₈ =O-tBDMS;R₃ =C₂ H₅ ; R₄ +R_(4a) =R₆ +R_(6a) =O; R₇ =OCH₃ ; ₋₋ -- -- =sb; n=2;

    ______________________________________    ex:     isomer  R.sub.5         starting material:    ______________________________________    59      C       OH              Ex. 1e     60a     B       OH                                    Ex. 1d    60b     B       --O--tBDMS    ______________________________________

EXAMPLE 61

Compound of formula III (R₁ =OH; R₂ =O-tBDMS; R₃ =C₂ H₅ ; R₄ +R_(4a) =O;R"₅ =R"₆ =OH; R₇ =OCH₃ ; ₋₋ -- -- =sb; n=2; R_(1a) =R_(2a) =H) (partialdeprotection)

3 ml of 40% aqueous hydrofluoric acid are added to a solution of 0.5 gof the compound of formula III (R₁ =R₂ =O-tBDMS; R₃ =C₂ H₅ ; R₄ +R_(4a)=O; R"₅ =R"₆ =OH; R₇ =OCH₃ ; ₋₋ -- -- =sb; n=2; R_(1a) =R_(2a) =H) in 30ml of acetonitrile. The reaction mixture is stirred for 5 minutes atroom temperature, then partitioned between saturated aqueous NaHCO₃-solution and ethyl acetate, the organic phase is separated, washed withsaturated aqueous NaHCO₃ -solution and several times with water, driedover Na₂ SO₄, filtered and evaporated under vacuum. Chromatography ofthe residue (n-hexane/ethyl acetate=1/2) gives the title substance as acolourless foam.

Analogously as described in example 61 the following compounds areobtained in form of colourless foams (R₁ =OH; R₄ +R_(4a) =O; R₇ =OCH₃ ;₋₋ -- -- =sb; n=2; R_(1a) =R_(2a) =H):

    __________________________________________________________________________                                   R.sub.5                                         R.sub.6                                   R'.sub.5                                         R'.sub.6    ex:       form.            isomer                 R.sub.2 R.sub.3   R".sub.5                                         R".sub.6                                             R.sub.6a                                                 R.sub.8 R.sub.8a                                                             start.    __________________________________________________________________________                                                             mat.    62 III  --   --O--tBDMS                         --CH.sub.2 CH═CH.sub.2                                   OH    OH  --  --      --  Ex. 3a    63 II   A    --O--tBDMS                         --CH.sub.2 CH═CH.sub.2                                   OH    OH  --  --      --  Ex. 3b    64 I    A    --O--tBDMS                         --CH.sub.2 CH═CH.sub.2                                   OH    O       OH      H   Ex. 3c    65 III  --   --O--tBDMS                         --C.sub.2 H.sub.5                                   OCH.sub.3                                         OH  --  --      --  Ex. 30    66 I    A    --O--tBDMS                         --C.sub.2 H.sub.5                                   OCH.sub.3                                         O       OH      H   Ex. 29    67 I    A    --O--tBDMS                         --C.sub.2 H.sub.5                                   OH    O       O--Im   H   Ex. 33    68 I    A    --O--tBDMS                         --C.sub.2 H.sub.5                                   OH    O       O           Ex. 50    69a       I    A    --O--tBDMS                         --C.sub.2 H.sub.5                                   O--tBDMS                                         O       --O--tBDMS                                                         H   Ex. 58a    69b       I    A    OH      --C.sub.2 H.sub.5                                   O--tBDMS                                         O       --O--tBDMS                                                         H   Ex. 58a    69c       I    A    OH      --C.sub.2 H.sub.5                                   O--tBDMS                                         O       OH      H   Ex. 58a    69d       I    A    --O--tBDMS                         --C.sub.2 H.sub.5                                   O--tBDMS                                         O       OH      H   Ex. 58a    70 I    A    --O--tBDMS                         --C.sub.2 H.sub.5                                   OH    O       OH      H   Ex. 1c    __________________________________________________________________________                                                             a)     a) Deprotection gives the compound of Example 6c (= Example 73)

EXAMPLE 71

Compound of formula I (R₁ =R₂ =R₅ =R₈ =OH; R₃ =C₂ H₅ ; R₄ +R_(4a) =R₆+R_(6a) =O; R₇ =OCH₃ ; R_(1a) =R_(2a) =R_(8a) =H; ₋₋ -- -- =sb; n=2;diastereoisomer B) (deprotection)

3 ml of 40% aqueous hydrofluoric acid are added to a solution of 0.5 gof the compound of formula I (R₁ =R₂ O-tBDMS; R₃ C₂ H₅ ; R₄ +R_(4a) =R₆+R_(6a) =O; R₅ =R₈ =OH; R₇ =OCH₃ ; R_(1a) =R_(2a) =R_(8a) =H; ₋₋ -- --=sb; n=2; diastereoisomer B) in 30 ml of acetonitrile. The reactionmixture is stirred for 4 hours at room temperature, then partitionedbetween saturated aqueous NaHCO₃ -solution and ethyl acetate, theorganic phase is separated, washed with saturated aqueous NaHCO₃-solution and several times with water, dried over Na₂ SO₄, filtered andevaporated under vacuum. Chromatography of the residue (n-hexane/ethylacetate=1/2) gives the title substance as a colourless foam.

      - Analogously as described in example 71 the following compounds are     obtained in form of colourless foams      (R.sub.7 = OCH.sub.3 ; R.sub.2a = H;   = sb; n =      2):                              R.sub.5 R.sub.6               R'.sub.5 R'.sub.6      ex: form. isomer R.sub.1 R.sub.1a R.sub.3 R.sub.2 R.sub.4 R.sub.4a     R".sub.5 R".sub.6 R.sub.6a R.sub.8 R.sub.8a start. mat.       72 II A OH H --C.sub.2      H.sub.5 OH O OH OH -- -- -- Ex. 1b                73 I A OH H --C.sub.2     H.sub.5 OH O OH O OH H Ex. 1c, 8,                  48 or 70       74 III -- OH H --C.sub.2      H.sub.5 OH O OH OH -- -- -- Ex. 1a              75 I C OH H --C.sub.2     H.sub.5 OH O OH O OH H Ex. 1e or 115       76 III -- OH H --CH.sub.2 CH═CH.sub.2 OH O OH OH -- -- -- Ex. 3a     or 62       77 II A OH H --CH.sub.2 CH═CH.sub.2 OH O OH OH -- -- -- Ex. 3b or     63       78 I A OH H --CH.sub.2 CH═CH.sub.2 OH O OH O OH H Ex. 3c or 64           79 I C OH H --CH.sub.2 CH═CH.sub.2 OH O OH O OH H Ex. 3d             80 III -- --O--SO.sub.2 --CH.sub.3 H --C.sub.2 H.sub.5 OH O OH     OH -- -- -- Ex. 4       81 III -- --O--SO.sub.2 --CH.sub.3 H --CH.sub.2 CH═CH.sub.2 OH O     OH OH -- -- -- Ex. 5       82 I C OH H --C.sub.2      H.sub.5 OH O OH OH H OH H Ex. 19      83 I B OH H --C.sub.2      H.sub.5 OH O OH OH H OH H Ex. 20                    84 I A OH H     --C.sub.2      H.sub.5 OH O OH OH H OH H Ex. 21                                 85 II     A OH H --C.sub.2      H.sub.5 OH OH H OH OH -- -- -- Ex. 28                     86 III -- OH     H --C.sub.2      H.sub.5 OH O OCH.sub.3 OH -- -- -- Ex. 30                      87 I A     OH H --C.sub.2      H.sub.5 OH O OCH.sub.3 O OH H Ex. 29                        88 I C OH H     --C.sub.2      H.sub.5 OH O OCH.sub.3 O OH H Ex. 31                             89 I A     OH H --C.sub.2      H.sub.5 OH O O--Bz O OH H Ex. 32c                           90 I A OH H     --C.sub.2      H.sub.5 OH O O--Bz O O--Bz H Ex. 32b                             91 I A     OH H --C.sub.2      H.sub.5 OH O OH O O--Im H Ex. 33 or 67                      92 I A O     --C.sub.2      H.sub.5 OH O OH O O Ex. 52                                       93 I A O     H H --C.sub.2      H.sub.5 OH O OH O O Ex. 50 a)                                94 I C OH     H --C.sub.2      H.sub.5 OH O OH O O Ex. 51                                     95 I A     OH H --C.sub.2      H.sub.5 OH O O--Ac O O--Ac H Ex. 37a                        96 I A OH H     --C.sub.2      H.sub.5 OH O OH O O--Ac H Ex. 37b                                97 I A     OH H --C.sub.2      H.sub.5 OH O O--Ac O OH H Ex. 37c                           98 II A OH     H --C.sub.2      H.sub.5 OH O O--Ac OH -- -- -- Ex. 37d                         99 I C     OH H --C.sub.2      H.sub.5 OH O O--Ac O O--Ac H Ex. 34                        100 III --     OH H --C.sub.2      H.sub.5 OH O --O--CO--O-- -- -- -- Ex. 13                  101 II A OH     H --C.sub.2      H.sub.5 OH O --O--CO--O-- -- -- -- Ex. 14                     102 I A     OH H --C.sub.2      H.sub.5 OH OH H OH O OH H Ex. 28                           103 I A OH H     --C.sub.2      H.sub.5 OH O --O--COOCH.sub.3 O OH H Ex. 39                     104 I A     OH H --C.sub.2      H.sub.5 OH O b) O OH H Ex. 44                              105 I A OH H     --C.sub.2      H.sub.5 OH O --O--CO--NH.sub.2 O OH H Ex. 45                    106 I A     OH H --C.sub.2 H.sub.5 OH O --O--CO--N(CH.sub.3).sub.2 O OH H Ex. 46          107 I C OH H --C.sub.2 H.sub.5 OH O --O--CO--NH.sub.2 O O Ex. 47b        108 I A OH H --C.sub.2      H.sub.5 OH O Cl O OH H Ex. 55                   109 I C OH H --C.sub.2     H.sub.5 OH O Cl O OH H Ex. 56      110 I A OH H --C.sub.2      H.sub.5 OH O --OCH.sub.3 O O Ex. 53               111 I C OH H --C.sub.2      H.sub.5 OH O --OCH.sub.3 O O Ex. 54      112 I A OH H --C.sub.2      H.sub.5 --O--CO--O-- H OH O OH H Ex. 15           113 I C OH H --C.sub.2      H.sub.5 --O--CO--O-- H OH O OH H Ex. 16      114 I C OH H --C.sub.2      H.sub.5 OH OH H OH OH H OH H Ex. 24b              115 I C OH H --C.sub.2      H.sub.5 OH O --O--BOC O OH H Ex. 43 a)      116 Ib C OH H --C.sub.2      H.sub.5 OH O -- -- -- O Ex. 47a                             (R'.sub.10     = H; X =      O)                                                               117     III -- OH H --C.sub.2 H.sub.5 --O--CO--O-- H OH OH -- -- -- Ex. 9a            118 I C OH H --C.sub.2      H.sub.5 OH OH H OH O OH H Ex. 24a     a) In equilibrium in solution with the hemiketal form (R.sub.5 + R.sub.8a     --O--; R.sub.8 = OH)     a) Deprotection gives the compound of Example 6e (= Example 75)     b) R.sub.5 = --O--CO--N!--(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --!     (4morpholinylcarbonyloxy)

The starting materials may be obtained as follows:

A) 33-O-Methanesulfonyl-24-O-tBDMS-FR 520

3 g of dimethylaminopyridine and 0.3 ml of methanesulfonic acid chlorideare added to a solution of 1 g of 24-O-tBDMS-FR 520 in 40 ml ofacetonitrile and stirred at room temperature for 2 hours. Then thereaction mixture is partitioned between saturated aqueous NaHCO₃-solution and ethyl acetate, the phases are separated, the organic phaseis washed with 1N hydrochloric acid and brine, dried over sodiumsulfate, filtered and evaporated under vacuum. Chromatography of theresidue (n-hexane/ethyl acetate=1/1) yields the title compound as acolourless foam.

B) 33-O-Methanesulfonyl-24-O-tBDMS-FK 506

Using 24-O-tBDMS-FK 506 as starting material and proceeding analogouslyas described in A) gives the title compound as a colourless foam.

C) Compound of formula V (R₁ =R₂ =O-tBDMS; R₃ =C₂ H₅ ; R₄ +R_(4a) =O; R₇=OCH₃ ; R₉ =CH₃ ; R_(1a) =R_(2a) =H; ₋₋ -- -- =sb; n=2; diastereoisomerC)

0.5 g of crown 18.6!ether and 0.7 g of 24,33-bis-O-tBDMS-FR 520 areadded to a suspension of 47 mg of powdered KOH in 40 ml oftetrahydrofuran. The reaction mixture is stirred for 20 minutes at roomtemperature, then partitioned between 1N hydrochloric acid and ethylacetate, the phases are separated, the organic phase is washed withbrine, dried over sodium sulfate and evaporated under vacuum. Theresidue is redissolved in 30 ml of dichloromethane and triturated with a1M solution of diazomethane in ether until the solution is light yellow.After evaporation of the solvent chromatography of the residue(n-hexane/ethyl acetate=2/1) gives the title compound as a colourlessfoam.

¹ H-NMR (CDCl₃): 5.14(d,J=7.5Hz,H-26); 4.99(d,J=10Hz,H-20);3.97(db,J=14Hz,H-6e); 3.81(s,COOCH₃);2.70(m,H-11).

D) Compound of formula V (R₁ =R₂ =O-tBDMS; R₃ =CH₂ --CH═CH₂ ; R₄ +R_(4a)=O; R₇ =OCH₃ ; R₉ =sb; n=2; diastereoisomer C) a =H; ₋₋ -- --

Using 24,33-bis-O-tBDMS-FK506 as starting material and proceedinganalogously as described in C) gives the title compound as a colourlessfoam.

E) Compound of formula V (R₁ =R₂ =O-tBDMS; R₃ =C₂ H₅ ; R₄ +R_(4a) =O; R₇=OCH₃ ; R₉ =CH₃ ;=sb; n=2; diastereoisomer A) -- -- --

2 g of calcium hydroxide are added to a solution of 3 g of24,33-bis-O-tBDMS-FR 520 in 60 ml of tetrahydrofuran and 15 ml of waterand stirred for 60 minutes at room temperature. Then the reactionmixture is partitioned between 0.5N hydrochloric acid and ethyl acetate,the phases are separated, the organic phase is dried and evaporatedunder vacuum. The residue is redissolved in 30 ml of dichloromethane andtriturated with a 1M solution of diazomethane in ether until thesolution is light yellow. After evaporation of the solventchromatography of the residue (n-hexane/ethyl acetate=2/1) gives thetitle compound as a colourless foam.

¹ H-NMR (CDCl₃) (mixture of rotamers=58/42): main rotamer: 5.20 (d,J=7.5Hz,H-26); 4.93(d,J=10 Hz,H-20); 4.04 (db,J=13 Hz,H-6e) ;3.83 (s,COOCH₃).secondary rotamer: 5.13 (d,J=10 Hz,H-26); 4.70 (d, J=10 Hz,H-20); 4.57(db, J=13 Hz,H-6e); 3.63 (s,COOCH₃).

Compound of formula V (R₁ =R₂ =O-tBDMS; R₃ =CH₂ --CH═CH₂ ; R₄ +R_(4a)=O; R₇ =OCH₃ ; R₉ =sb; =2; diastereoisomer A) 2a =H; ₋₋ ----

Using 24,33-bis-O-tBDMS-FK506 as starting material and proceedinganalogously as described in E) gives the title compound as a colourlessfoam.

G) Compound of formula IV (R₁ =O-tBDMS; R_(1a) =R_(2a) =R_(4a)=sb; n=2).2 +R₄ =O--CO--O; R₃ =C₂ H₅ ; ₋₋ -- --

Using the compound of formula IV (R₁ =O-tBDMS; R_(1a) =R_(2a) =R_(4a)=H; R₂ =R₄ =OH; R₃ =C₂ H₅ ; ₋₋ --=sb; n=2) as starting material andproceeding analogously as described in Example 13 the title compound isobtained as a colourless foam.

    __________________________________________________________________________    .sup.1 H-NMR-Spectra    (500 MHZ)    Example:         spectrum:    __________________________________________________________________________    1a   5.32(d, J=8.9Hz. H-29); 4.88(sb, H-26); 4.80(db, J=7.6Hz, H-20);         4.09(db.         J=13Hz, H-6e); 4.03(dxd, J=2.9/9.4Hz, H-14); 4.49 (sb, H-24);         3.38/3.33/3.32(3xOCH.sub.3).    1b, 2a         5.37(d, J=9.1Hz, H-29); 5.155(d, J=10.6Hz, H-26); 4.62(d, J=10.6Hz,         H-20);         4.11(dxd, J=3.2/10.4Hz, H-24); 4.015(dxd, J=4.7/13.3Hz, H-6e); 3.76         (d, J=8.5 Hz, H-14); 3.42/3.375/3.370(3xOCH.sub.3); 3.18(dxt,         J=3.6/13.3Hz,         H-6a).    1c, 2b         5.24(d, J=9Hz, H-29); 5.165(d, J=7.2Hz, H-26); 4.86(d, J=10Hz,         H-20); 4.27         (dxd, J=5/13Hz. H-6e), 4.155(m, H24); 3.68(txd, J=8/2Hz, H-14);         3.504/3.406/3.404(3xOCH.sub.3); 3.24(txd, J=13/3Hz, H-6a); 3.185(m,         H-21);         2.955(m, H-32); 2.76(dxdxd, J=2,5/11/16Hz, H-12); 2.67(dxd,         J=7/17Hz,         H-23).    1d   5.39(d, J=8.3Hz, H-29); 5.09(d, J=10.5Hz. H-26); 4.84(d, J=10.1Hz,         H-20);         4.37(dxd, J=4.2/12.7Hz, H-6e); 4.13(m, H-24); 3.40/3.36/3.35(3xOCH.su         b.3);    1E, 10         5.37(dxq, J=9/1.3Hz, H-29); 5.18(d, J=10.7Hz, H-26); 4.73(d,         J=10.8Hz,         H-20); 4.37(dxd, J=4.9/13.3Hz, H-6e); 4.12(dxd, J=4.4/11.1Hz;         H-24);         3.60/3.41/3.39(3xOCH.sub.3).    3a   5.73(dxdxt, J=10.2/17.1/7Hz, H-37); 5.31(d, J=9.1Hz, H-29);         5.02(dxq,         J=17.1/1.8Hz, H-38tr.); 4.94(dxq, J=10.2/1.8Hz, H-38cis); 4.88(s,         H-26);         4.80(d, J=9Hz, H-20); 4.54(sb, H-24); 4.09(db, J=13Hz, H-6e);         4.02(dxd,         J=2.7/9.4Hz, H-14); 3.38/3.34/3.21(3xOCH.sub.3).    3b, 12b         5.71(dxdxt, J=10.2/17.1/6.9Hz, H-37); 5.37(d, J=8.2Hz, H-29);         5.175(d,         J=10.8Hz, H-26); 5.025(dxq, J=17.1/1.8Hz, H-38tr.); 4.98(dxq,         J=10.2/1.8Hz,         H-38cis); 4.655(d, J=10.7Hz, H-20); 4.11(dxd, J=3/10.6Hz, H-24);         4.015         (dxd, J=4.4/13.2Hz, H-6e), 3.755(d, J=8.5Hz, H-14); 3.18(dxt,         J=3.7/13.2Hz,         H-6a).    3c.sup.2)         5.74(dxdxt, J=10/17/7Hz, H-37); 5,25(d, J=9Hz, H-29); 5.17(d, J=7Hz,         H-26)    12a.sup.2)         5.09(dxd, J=2/17Hz, H-38tr.); 4.99(dxd, J=2/10Hz, H-38cis); 4.89(d,         J=10Hz,         H20); 4.28(dxd, J=4/13Hz, H-6e); 4.15(m, H-24); 3.70(t, H-14);         3.52/2x3.42         (3xOCH.sub.3); 3.26(txd, J=13/3Hz, H-6a); 2.97(m, H-32).    3d, 11         5.71(dxdxt, J=10.1/17.1/7.0Hz, H-37); 5.37(d, J=9Hz, H-29); 5.18(d,         J=10.6Hz, H-26); 5.04(dxq, J=17.1/1.9Hz. H-38tr.); 4.99(dxq,         J=10.1/1.9Hz,         H-38cis); 4.75(d. J=10.9Hz, H-20); 4.36(dxd, J=4.8/13.3, H-6e);         4.12(dxd,         J=4.2/11Hz, H-24); 3.59/3.40/3.38(3xOCH.sub.3);    4.sup.2)         5.31(d, J=9Hz, H-29); 4.31(dxdxd, J=5/8/11Hz, H-33); 4.03(dxd,         J=3/10Hz,         H-14); 3.40/3.36/3.23(3xOCH.sub.3); 3.06(s, O-mesyl).    5.sup.2)         5.73(dxdxt, J=10/17/7Hz, H-37); 5.30(d, J=9Hz, H-29); 5.03(dxq,         J=17/2Hz,         H-38tr.); 4.96(dxq, J=10/2Hz, H-38cis); 4.51(m, H-24); 4.31(m,         H-32); 4.02         (dxd, J=3/9.5Hz, H-14); 3.40/3.36/3.22(3xOCH.sub.3); 3,06(s,         0-mesyl).    6a, 74         5.27(d. J=9.1Hz, H-29); 5.09(s, H-26); 5.12(d, J=10Hz, H-20);         4.08(db,         J=13Hz, H-6e); 4.02(dxd, J=5.5/9.5Hz, H-14); 3.99(m, H-24);         3.43/3.38/3.33         (3xs, 3xOCH.sub.3)    6b, 72         5.33(d, J=7Hz, H-26); 5.31(d, J=9Hz, H-29); 4.79(d, J=10Hz, H-20);         2.91         (dxd, J=7/16Hz, H-23a).    6c, 73         5.12(d, J=9Hz, H-29); 5.115(d, J=3Hz, H-26); 5.00(d, J=10HZ, H-20);         4.30         (dxd, J=4/13Hz, H-6e); 3.87(m, H-24); 3.52(t, H-14); 3.175(m, H-21);         3.03         (m, H-32); 3.46/3.42/3.39(3xs, 3xOCH.sub.3);    6d.sup.2)         5.36(d, J=9Hz, H-29); 5.18(d, J=9Hz, H-26); 4.80(d, J=10Hz, H-20);         4.38(d,    71.sup.2)         J=13Hz, H-6e); 4.01(m, H-24); 3.50/3.42/3.38(3xOCH.sub.3).    6e.sup.7), 75.sup.7)         5.36(d; J=9Hz; H-29); 5.18(d; J=9Hz; H-26); 4.80(d; J=10Hz; H-20);         4.38(d; J=13Hz; H-6equ.); 3.38/3.42/3.50(3xs; 3x-OCH.sub.3).    7c.sup.2), 78.sup.2)         5.70(dxdxt, J=10/17/7Hz, H-37); 4.30(dxd, J=4/13Hz, H-6e); 3.87(m,         H-24);         3.54(t, H-14); 3.03(m, H-32); 3.47/3.42/3.39(3xs, 3xOCH.sub.3);    9b, 15         4.48(dxdxd, J=12.5/2.6/0.8Hz, H-22); 4.27(dxdb, J=4.5/13Hz,         H-6equ.); 3.94         (dxdxd, J=10.1/3.4/0.6Hz, H-24); 3.42/3.408/3.39(3xs, 3xOCH.sub.3);         3.32(m,         H-14); 3.12(txd, J=8.8/2.4Hz, H-13); 2.97(m, H-32); 2.90(d,         J=9.2Hz,         H-14).    13   5.38(H-29); 4.91(H-20 and H-26); 4.33(H-24); 4.11(db, J=13Hz,         H-6e);         4.04(dxd, J=2.6/9.5Hz, H-14); 3.39/3.34/3.30(3xs, 3xOCH.sub.3);    14   5.33(d, J=9.1Hz, H-29); 5.26(d, J=10.8Hz, H-26); 4.77(d, J=10.4Hz,         H-20);         4.13(dxd, J=3.9/13.5Hz, H-6e); 4.08(dxd, J=2.9/10.8Hz, H-24);         1.44(d,         J=6.9Hz, 11-CH.sub.3).    19   5.28(db, J=8.4Hz. H-29); 5.15(db, J=7Hz, H-26); 4.78(sb; H-20);         2.95(m,         H-32).    20   5.32(d. J=8.9Hz, H-29); 5.27(d, J=5.7Hz, H-26); 4.91(d, J=10HZ,         H-20); 3.98         (d. J=4.2Hz, H-10); 1.38(d, J=6.8Hz, 11-CH.sub.3).    21   5.37(d, J=9Hz, H-29); 5.12(d. H=10.5Hz, H-26); 4.68(d, J=10.5Hz,         H-20);         4.19(d, J=7.3Hz, H-10); 4.10(dxd, J=4.5/10.5Hz, H-24); 3.97(dxd,         J=3.5/13Hz, H-6e); 3.51/3.43/3.39(3xs, 3xOCH.sub.3); 2.96(dxdxd,         J=4.518.5/11.3Hz, H-32); 1.83(d, J=1Hz, 19-CH.sub.3); 1.59(d,         J=1.2Hz, 28-CH.sub.3);         1.33(d, J=7Hz, 11-CH.sub.3); 0.83(t, J=7Hz, H-37); 0.77(d, J=6.5Hz,         25-CH.sub.3);    22   5.36(d, J=9,1Hz, H-29); 5.17(d, J=9.9Hz, H-20); 4.85(s, H-26);         4.00(dxd,         J=3.7/13Hz, H-6e); 3.95(m, H-22); 3.88(dxdxd, J=2.1/4.8/10.4; H-15         or         H-24); 3.66(dxd, J=2.1/11Hz, H-24 or H-15); 3.40/3.37/3.30(3xs,         3xOCH.sub.3);         3.26(dxt, J=5.1/9.9Hz, H-13); 2.93(dxdxd, J=5/8/11Hz, H-32).    27.sup.4)         5.24(d, J=9Hz, H-29); 5.14(d, J=4.2Hz, H-26); 5.0(d, J=10Hz. H-20);         4.42         (db, J=5.8Hz, H-6equ.).    29   5.34(d, J=9Hz, H-29); 5.10(d, J=9.8Hz, H-26); 4.64(d, J=10.5Hz,         H-20); 4.31         (dxd, J=4/13Hz, H-6e); 4.09(dxd, J=4.8/10Hz, H-24);         3.58(15-OCH.sub.3),         3.39(32-OCH.sub.3); 3.30(13-OCH.sub.3); 3.16(9-OCH.sub.3);         1.82(19-CH.sub.3); 1.51         (28-CH.sub.3); 1.18(d, J=7Hz, 11-CH.sub.3).    30   5.42(H-29); 4.99(H-20); 4.84(H-26); 4.03(db, J=12Hz, H-6e); 2.97(m,         H-32).    31   5.38(d, J=9Hz, H-29); 5.12(d, J=10.5Hz, H-26); 4.74(d, J=10.7Hz,         H-20);         4.45(dxd, J=3/13Hz, H-6e); 4.12(dxd, J=4.4/10.2Hz, H-24);         3.58/3.40/3.37/3.17(4xs, 4xOCH.sub.3).    32a  5.37(d, J=9Hz, H-29); 4.93(d, J=11Hz, H-26); 4.65(d, J=10Hz, H-20);         4.34         (dxd,J=3/13Hz, H-6e), 4.13(dxd, J=3/11Hz, H-24); 5.44(dxd, J=2/8Hz,         H-14);         2x3.45/3.42(2xs, 3xOCH.sub.3); 2.97(m, H-32).    32b  5.33(d, J=8Hz, H-29); 5.11(d, J=10.6Hz, H-26); 4.60(d, J=10.6Hz,         H-20);         4.25(dxd, J=3.5/13.3Hz, H-6e); 4.11(dxd, J=3.4/10.6Hz, H-24);         5.48(d,         J=8.9Hz, H-14); 3.42/3.40/3.37(3xs, 3xOCH.sub.3); 2.97(m, H-32).    32c  5.47(d, J=9Hz, H-29); 5.11(d, J=11Hz, H-26); 4.58(d, J=10Hz, H-20);         4.25         (dxd, J=3/13Hz, H-6e); 4.08(dxd, J=3/11Hz, H-24); 3.60(d, J=8Hz,         H-14);         3.55/3.41/3.35(3xs, 3xOCH.sub.3); 2.98(m, H-32).    32d  5.42(d, J=9Hz, H-29); 5.25(b, H-26); 4.59(d, J=10HZ, H-20);         4.18(H-6e);         4.11(dxd, J=3/10Hz, H-24); 3.43/3.39/3.37(3xs, 3xOCH.sub.3).    33   8.20/7.48/7.09(imidazolyl-H); 5.37(d, J=8.9Hz, H-29); 5.27(dxd,         J=2/8.8Hz,         H-14); 4.88(d, J=10,5Hz, H-26); 4.62(d, J=10.3Hz, H-20); 4.34(dxd,         J=4.2/13.4Hz, H-6); 4.12(dxd, J=3.5/10.2Hz, H-24); 2x3.42/3.48(2xs,         3xOCH.sub.3).    34   5.37(d, J=9Hz, H-29); 5.17(dxd, J=3/8Hz, H-14); 5.10(d, J=10.3Hz,         H-26);         4.74(d, J=10.7Hz, H-20); 4.37(dxd, J=4.6/13.1Hz, H-6e); 4.11(dxd,         J=4.2/11Hz, H-24); 2x2.13(1xs, 2xCOCH.sub.3); 3.45/3.41/3.38(3xs,         3xOCH.sub.3).    35a  5.38(d, J=9.1Hz, H-29); 4.76(d, J=10.8Hz, H-20); 4.43(dxd,         J=3/13Hz,         H-6e); 4.13(dxd, J=4/10Hz, H-24); 3.55/3.41/3.40(3xs, 3xOCH.sub.3).    35b  5.39(d, J=8.9Hz, H-29); 5.13(d, J=10.4Hz, H-26); 4.79(d, J=10.1Hz,         H-20);         4.14(m, H-24); 3.46/3.42/3.39(3xs, 3xOCH.sub.3);    36a.sup.2)         5.39(d, J=9.5Hz, H-29); 5.05(d, J=10.4Hz, H-26); 4.95(dxd, J=2/8Hz,         H-14);         4.73(d, J=10.7Hz, H-20); 4.38(dxd, J=3/13Hz, H-6e); 4.12(m, H-24);         3.56/3.45/3.39/3xs, 3xOCH.sub.3); 3.25/3.13(2xs, 2xCH.sub.3 SO.sub.2         -).    36b.sup.2)         5.38(d, J=8.5Hz, H-29); 5.17(d, J=10.5Hz, H-26); 4.96(dxd, J=2/8Hz,         H-14);         4.73(d, J=11.5Hz, H-20); 4.35(dxd, J=3/13Hz, H-6e); 4.12(m, H-24);         3.59 /3.41/3.40(3xs, 3xOCH.sub.3); 3.11(s, CH.sub.3 SO.sub.2 -).    37a  5.43(d, J=8.7Hz, H-29); 5.03(m, 2H, H-14 and H-26); 4.57(d,         J=10,1Hz,         H-20); 4.20(dxd, J=13.6/4.7Hz, H-6e),, 4.06(dxd, J=11.8/3.3Hz,         H-24);         3.52/3.39/3.30(3xs, 3xOCH.sub.3); 2.16/2.13(2xs, 2xOAc).    37b  5.34(d, J=9Hz, H-29); 5.17(dxd, J=7.2/3.6Hz, H-14); 4.94(d, J=9.8Hz,         H-26);         4.65(d, J=9.8Hz, H-20); 4.30(dxd, J=13.6/4.5Hz, H-6e); 4.11(dxd,         J=10/3.6Hz, H-24).    37c  5.43(d, J=9Hz, H-29); 5.03(d, J=10,7Hz, H-26) 4.61(d, J=10.5Hz,         H-20);         4.21(dxd, J=13.5/4.6Hz, H-6e); 4.07(dxd, J=10.7/3.3Hz, H-24);         3.61/3.40/3.33(3xOCH.sub.3); 2.11(s, OAc).    37d  5.4(d; J=9.2Hz; H-29); 5.02(sb; H-26); 4.58(db; J=10Hz; H-20).    39   5.44/5.04/4.57(3xd, J=8.2/10.8/10.1Hz, H-29/26/20); 3.74(s,         -COOCH.sub.3);         3.54/3.41/3.22(3xs, 3xOCH.sub.3);    41   7.93(d, J=1Hz, CHO); 5.53/5.28/4.86(3xd, J=7.9/10.4/10.6Hz,         H-29/26/20);         4.37(dxd, J=13.3/4.7Hz, H-6equ.); 4.08(m, H-24).    43   5.38(d, J=9.9Hz, H-29); 5.1(d, J=10.4Hz, H-26); 4.73(d, J=10.8Hz,         H-20);         4.4(dxd, J=13.2/4.7Hz, H-6equ.); 4.12(dxd, J=7.1/4.1Hz, H-24);         1.41(s.         BOC).    44   5.43(d, J=8.9Hz, H-29); 4.98(d, J=10.8Hz, H-26); 4.58(d, J=10,4Hz,         H-20);         4.22(m, H-6equ.); 4.07(dxd, J=3.3/10.9Hz, H-24); 3.54/3.41/3.23(3xs,         3xOCH.sub.3).    45.sup.5)         5.48(dxd, J=1/8.9Hz, H-29); 4.66(d, J=10.2Hz, H-20);         4.21/4.14(db/dxd;         H-6equ./H-24).    50   mixture; ketone/hemiketal = 40/60         ketone; 5.37(d, J=8.9Hz, H-29); 4.96(d, J=10.7Hz, H-26); 4.62(d,         J=10.5Hz,         H-20); 4.46(d, J=10.4Hz, H-15); 4.12(dxd, J=10.5/3.3Hz, H-24).         hemiketal; 5.05(d, J=8.9Hz, H-29); 5.11(d, J=3.5Hz, H-26); 4.81         J=10.2Hz, H-20); 3.51(dxd, J=9.1/2.8Hz, H-15); 3.77(dxd,         J=11.7/4.6Hz,         H-13); 3.56(m, H-24).    51   5.38(d, J=9.0Hz, H-29); 5.22(d, J=10.2Hz, H-26); 4.79(d, J=10.7Hz,         H-20);         4.41(dxd, J=11.9/3.2Hz, H-13); 4.38(dxd, J=13/4Hz, H-6e); 4.15(dxd,         J=10.7/4.3Hz, H-24); 4.08(dxd, J=9.2/3.5Hz, H-15);         3.42/3.40/3.37(3xs,         3xOCH.sub.3); 3.23(dxdxd, J=10.9/8.5/5.6Hz, H-21); 3.17(txd,         J=13.2/3.6Hz,         H-6a).    52   mixture; ketone/hemiketal = 40/60         ketone; 5.38(d, J=9Hz, H-29); 4.92(d, J=10.7Hz, H-26); 4.60(d,         J=10Hz,         H-20); 4.47(d, J=9.5Hz, H-15).         hemiketal; 5.08(d, J=9Hz, H-29); 5.11(d, J=4.2Hz, H-26); 4.83(d,         J=10Hz,         H-20); 3.76(dxd, J=11.6/4.6Hz, H-13).    58a  5.4(dxd, J=8.9/1.1Hz, H-29); 5.12(d, J=10.8Hz, H-26); 4.57(db,         J=10.5Hz,         H-20), 4.24(dxd, J=13.6/4.8Hz, H-6equ.); 4.07(dxd, J=11/3.5Hz,         H-24); 3.63         (d, J=8.5Hz, H-14); 3.52/3.40/3.21(3xOCH.sub.3);    58b  5.34(dxd, J=8.9/1.1Hz, H-29); 4.89(d, J=10.2Hz, H-26); 4.62(d,         J=10.3Hz,         H-20); 4.3(dxd, J=4.3/13.8Hz, H-6equ.); 2,94(m, H-32); 2.84(dxd,         H-23a).    60a  5.32(d; J=9Hz, H-29); 5.18(d, J=9.1Hz, H-26); 4.85(d, J=10.4Hz,         H-20); 4.37         (db, J=10.4Hz, H-6equ.); 4.16(m, H-24); 3.44/3.41/3.36(3xs,         3xOCH.sub.3);    60b  5.34(d, J=9Hz, H-26); 5.22(d, J=9.9Hz, H-29); 4.92(d, J=10,4Hz,         H-20); 4.36         (db, J=11Hz, H-6equ.); 4.11(m, H-24); 3.40/3.38/3.36(3xs,         3xOCH.sub.3);    61   5.35(d, J=9Hz, H-29); 4.88(sb, H-26); 4.81(d, J=8.2Hz, H-20);         4.53(H-24);         4.11(db, J=13Hz, H-6e); 4.03(dxd, J=2.8/9.5Hz, H-14);         3.40/3.34/3.23(3xs,         3xOCH.sub.3).    62.sup.2)         5.74(dxdxt, J=10/17/7Hz, H-37); 5.34(d, J=9Hz, H-29); 4.80(d, J=9Hz,         H-20);         4.54(H-24); 4.02(dxd, J=2.5/10Hz, H-14); 3.41/3.34/3.22(3xs,         3xOCH.sub.3);    63.sup.2)         5.72(dxdxt; J=10/17/7Hz, H-37); 5.41(d, J=9Hz, H-29); 5.18(d,         J=10.5Hz,         H-26); 5.04(dxq, J=17/2Hz, H-38tr.); 4.98(dxq, J=10/2Hz, H-38cis);         4.65(d,         J=10Hz, H-20); 4.12(dxd, J=3/11Hz, H-24); 4.04(dxd, J=3/13Hz, H-6e);         3.19         (dxt, J=3/13Hz, H-6a); 3.02(m, H-32).    64.sup.2)         5.75(dxdxt, J=10/17/7Hz, H-37); 5.28(d, J=9Hz, H-29); 5.17(d, J=7Hz,         H-26);         5.09(dxd, J=2/17Hz, H-38tr.); 4.98(dxd, J=2/10Hz, H-38cis); 4.88(d,         J=10Hz,         H-20); 4.28(dxd, J=4/13Hz, H-6e); 4.15(m, H-24), 3.70(t, H-14);         2x3.42/3.52(2xs, 3xOCH.sub.3); 3.25(txd, J=13/3Hz, H-6a); 3.03(m,         H-32).    65   5.43(d, J=8.8Hz, H-29); 4.97(d, J=9.5Hz, H-20); 4.82(H-26);         4.30(H-24);         4.04(db, J=13Hz, H-6e); 3.79/3.41/3.35/3.33(4xs, 4xOCH.sub.3);    67   8.20/7.48/7.08(imidazolyl-H); 5.37(d, J=9Hz, H-29); 5.26(dxd,         J=1.9/8.9Hz,         H-14); 4.86(d, J=10.6Hz, H-26); 4.60(d, J=10.3Hz, H-20); 4.34(dxd,         J=4.5/13.6Hz, H-6e); 4.12(dxd, J=3.3/10.2Hz, H-24);         3.48/3.42/3.41(3xs,         3xOCH.sub.3).    68   mixture; ketone/hemiketal = 60/40         ketone; 5.38(d, J=9Hz, H-29); 4.98(d, J=10.5Hz, H-26); 4.66(d,         J=10.3Hz,         H-20); 4.46(d, J=8.9Hz, H-15).         hemiketal; 5.11(d, J=9Hz, H-29); 5.13(d, J=4.4Hz, H-26); 4.87(d,         J=10Hz,         H-20); 3.76(dxd, J=11.4/4.4Hz, H-13).    69a  5.36(d, J=8.2Hz, H-26); 4.86(db, J=10Hz, H-29); 4.31(dxd,         J=13.3/4.3Hz,         H-6equ.); 4.1(dxd, J=10,2/3.6Hz, H-24); 3.54/3.41/3.32(3xs,         3xOCH.sub.3).    69c  5.38/5.18/4.71(3xd, J=8.5/9.1/10.4Hz, H-26/29/20);         3.58/3.42/3.31(3xs,         3xOCH.sub.3).    69d  5.42/5.13/4.59(3xd, J=9.8/10.8/10.6Hz, H-29/26/20); 4.08(dxd,         J=11/3.5Hz,         H-24); 3.6/3.39/3.32(3xs, 3xOCH.sub.3).    80.sup.2)         4.35(dxdxd, J=5/8/11Hz, H-33); 3.41/3.37/3.34(3xs, 3xOCH.sub.3);         3.07(s,         CH.sub.3 SO.sub.2 -).    81.sup.2         5.73(dxdxt, J=10/17/7Hz, H-37); 5.22(d, J=9Hz, H-29); 4.34(m,         H-33);         3.41/3.36/3.33(3xs, 3xOCH.sub.3), 3.08(s, CH.sub.3 SO.sub.2 -).    82   5.20(s, H-26); 5.17(d, J=9Hz, H-29); 4.98(d, J=9.7Hz, H-20);         4.12(H-6e);         4.10(d, J=4.6Hz, H-10); 4.04(m, H-24); 3.40/3.36/3.30(3xs,         3xOCH.sub.3); 1.685         (d, J=1Hz, 28-CH.sub.3); 1.66(d, J=1Hz, 19-CH.sub.3); 1.28(d,         J=6.7Hz, 11-CH.sub.3); 0.99         (d, J=6.5Hz, 17-CH.sub.3); 0.955(d, J=7Hz, 25-CH.sub.3); 0.86(t,         J=7.4Hz, H-37).    83   5.10(d, J=9Hz, H-29); 5.12(s, H-26); 4.94(d, J=9.5Hz, H-20);         4.09(db,         J=13Hz, H-6e); 3.94(d, J=3Hz, H-10); 3.73(m, H-24);         3.41/3.35/3.33(3xs,         3xOCH.sub.3); 1.64(d, J=1Hz, 28-CH.sub.3); 1.58(d, J=1Hz,         19-CH.sub.3); 1.40(d, J=6.8Hz,         11-CH.sub.3); 0.99 and 0.99(d and d, J=7 and 7Hz, 17-CH.sub.3 and         25-CH.sub.3); 0.87(t,         J=7.4Hz, H-37).    84.sup.3)         5.22(d, J=9Hz, H-29); 5.04(d, J=6.6Hz, H-26); 4.80(d, J=10Hz, H-20);         4.15         (s, H-10); 4.00(m, H-24); 3.94(dxd, J=3/13Hz, H-6e);         3.47/3.43/3.41(3xs,         3xOCH.sub.3); 3.05(dxdxd, J=4.3/8.8/11.3Hz, H-32); 2.85(dxd,         J=7.9/16.7Hz,         H-23a); 2.51(dxd, J=5.1/16.7Hz, H-23b); 2.32(m, H30); 1.74(d,         J=1Hz,         19-CH.sub.3); 1.63(d, J=1Hz, 28-CH.sub.3); 1.29(d, J=7Hz,         11-CH.sub.3); 0.85(t, J=7.4Hz,         H-37).    85   5.27(s, H-26); 5.16(d, J=9.1Hz, H-29); 5.13(d, J=9.5Hz, H-20);         4.07(dxd,         J=4.9/13.5Hz, H-6e); 3.95(m, H-24); 3.90(m, H-22); 3.62(dxdxd,         J=2.4/4.4/8.2Hz, H-15); 3.54(dxd, J=2.3/9.5Hz, H-14); 3.23(dxt,         J=5/10Hz,         H-13); 3.41/3.40/3.38(3xs, 3xOCH.sub.3); 1.70(d, J=1Hz,         28-CH.sub.3); 1.58(s,         19-CH.sub.3); 1.10(d, J=7Hz, 11-CH.sub.3); 0.98(d, J=7Hz,         25-CH.sub.3), 0.95(d, J=7Hz,         17-CH.sub.3); 0.89(t, J=7.5Hz, H-37).    86   5.28(d, H-29); 5.27(s, H-26); 5.17(d, J=10.1Hz, H-20); 3.94(db,         J=13Hz,         H-6e); 3.8(m, H-24); 3.58(dxd, J=5.7/9.5Hz, H-14); 3.81(s,         9-OCH.sub.3); 3.50         (s, 15-OCH.sub.3); 3.41(s, 32-OCH.sub.3); 3.34(s, 13-OCH.sub.3);         3.10(dxdxd,         J=2.5/6/10Hz, H-15); 3.02(dxdxd, J=4.3/8.8/11.2Hz, H-32); 2.30(dxt,         J=3.6/13Hz, H-6a); 1.75(d, J=1Hz, 19-CH.sub.3); 1.69(d, J=1,1Hz,         28-CH.sub.3); 1.16         (d, J=6.9Hz, 11-CH.sub.3). 1.10(d, J=7Hz, 25-CH.sub.3). 0.99(d,         J=6.4Hz, 17-CH.sub.3);         0.89(t, J=7.4Hz, H-37).    87   5.23(d, J=9Hz, H-29); 5.19(d, J=5.2Hz, H-26); 4.95(d, J=10Hz, H-20);         4.38         (dxd, J=4/13Hz, H-6e); 3.55/3.40/3.31/3.12(4xs, 4xOCH.sub.3).    88.sup.2         5.30(d, J=9Hz, H-29); 5.02(d, J=8,2Hz, H-26); 4.83(d, J=9.7Hz,         H-20); 4.48         (dxd, J=3/13Hz, H-6e); 3.97(m, H-24); 2x3.40/3.22/3.19(3xs,         4xOCH.sub.3);    89   5.28(d, J=9Hz, H-29); 5.25(d, J=6Hz, H-26); 4.84(d, J=10Hz, H-20);         4.30         (dxd, J=3/13Hz, H-6e); 4.02(m, H-24); 3.71(d, J=8Hz, H-14); 3.04(m,         H-32);         3.59/3.44/3.38(3xs, 3xOCH.sub.3);    90.sup.2)         5.32(d, J=8.7Hz, H-29); 5.22(d, J=6.8Hz, H-26); 4.77(d, J=10.3Hz,         H-20);         4.29(db, J=13Hz, H-6e); 4.03(m, H-24); 5.45(d, J=8.6Hz, H-14);         3.44/3.43/3.38(3xs, 3xOCH.sub.3).    91   8.20/7.48/7.08(imidazolyl-H); 5.22(d, J=9.1Hz, H-29); 5.31(dxd,         J=2.8/8.2Hz, H-14); 5.09(d, J=6.0Hz, H-26); 4.88(d, J=9.7Hz, H-20);         4.31         (dxd, J=3/12Hz, H-6e); 4.08(m, H-24); 2x3.43/3.41(2xs,         3xOCH.sub.3);    92   mixture; ketone/hemiketal = 34/66         ketone; 5.25(d, J=9Hz, H-29); 5.07(d, H-26); 4.84(d, J=9.7Hz,         H-20).         hemiketal; 5.04(d, J=9Hz, H-29); 5.15(s, H-26); 4.76(d, H-20);         3.57(dxd,         J=9.8/2.6Hz, H-15); 3.75(dxd, J=11.7/4.6Hz, H-13).    93   mixture; ketone/hemiketal = 1/1.8         ketone; 5.25(d, J=9.2Hz, H-29); 5.08(d, J=6.6Hz, H-26); 4.85(d,         J=9.6Hz,         H-20).         hemiketal; 5.04(d, J=9.3Hz, H-29); 5.15(s, H-26); 4.76(d, J=10.2Hz,         H-20);         3.57(dxd, J=10.1/2.4Hz, H-15); 3.76(dxd, J=11.7/4.5Hz, H-13).    94   5.28(d, J=9.1Hz, H29); 5.19(d, J=5.9Hz, H26); 4.97(d, J=9.7Hz, H20);         4.40         (m, H6e); 4.29(dxd, J=8.9/4.5Hz, H13); 3.92(t, J=7Hz, H15); 3.87(m,         H24);         3.41/3.39/3.38(3xs, 3xOCH.sub.3); 3.24(m, H21).    95   5.28(d, J=9.0Hz, H-29); 5.12(d, J=7.9Hz, H-14); 5.10(d, J=7.5Hz,         H-26);         4.82(d, J=10.4Hz, H-20); 4.23(dxd, J=13/3Hz; H-6e); 4.02(t, H24);         3.50/3.41/3.30(3xs, 3xOCH.sub.3); 2.15/2.06(2xOAc).    96   5.20(m, 2H, H-29 and H-14); 5.10(d, J=6Hz, H-26); 4.90(d, J=9.7Hz,         H-20);         4.30(dxd, J=13.3/4.5Hz, H-6e); 4.08(m, H-24); 3.45/3.44/3.41(3xs,         3xOCH.sub.3); 3.20(m, H-21); 2.12(OAc).    97   5.28(d, J=8.7Hz, H-29); 5.09(d, J=7.2Hz, H-26); 4.85(d, J=10.4Hz,         H-20);         4.23(dxd, J=13/3Hz, H-6e); 4.05(m, H-24); 3.59/3.41/3.33(3xs,         3xOCH.sub.3);         3.27(m, H-21); 2.05(s, OAc);    98   5.37(d, J=5.4Hz, H-26); 5.32(d, J=8.7Hz, H-29); 4.78(d, J=10.2Hz,         H-20);         4.16(dxd, J=13/3Hz, H-6e); 4.00(m, H-24); 3.42/3.38/3.36(3xs,         3xOCH.sub.3),         2.21(s, OAc).    99   5.31(d, J=9Hz, H-29); 5.19(d, J=6Hz, H-26); 5.08(dxd, J=5/7Hz,         H-14); 4.80         (d, J=10Hz, H-20); 4.38(dxd, J=13/3Hz, H-6e); 3.81(m, H-24).    100  5.28(d, J=9.1Hz, H-29); 4.96(d, J=10.1Hz, H-20); 4.76(d, J=4.8Hz,         H-26);         4.21(m, H-24); 3.99(dxd, J=2.3/9.7Hz, H-14); 3.40/3.35/3.34(3xs,         3xOCH.sub.3);         3.02(dxdxd, J=4.3/8.8/11.3Hz, H-32); 1.80(d, J=1Hz, 19-CH.sub.3);         1.74(d,         J=1.1Hz, 28-CH.sub.3); 1.16(d, J=7Hz, 11-CH.sub.3); 0.94(d, J=7Hz,         25-CH.sub.3 and         17-CH.sub.3); 0.87(t, J=7.4Hz, H-37).    101  5.32(d, J=9Hz, H-29); 5.23(d, J=7.8Hz, H-26); 4.85(d, J=10.2Hz,         H-20); 4.17         (dxd, J=4/13.5Hz, H-6e); 4.02(m, H-24); 3.60(m, H-15); 3.51(dxd,         J=1.4/9.5Hz, H-14); 1.78(d, J=1Hz, 19-CH.sub.3); 1.44(d, J=6.9Hz,         11-CH.sub.3);    102.sup.2)         5.09(sb, H-26); 4.99 and 4.91(d and d; J=10 and 10Hz, H-20 and         H-29); 4.33         (db, J=13Hz, H-6e); 3.66(m, H-22); 3.57(m, H-24); 3.43/3.38/3.36(3xs,         3xOCH.sub.3).    103  5.215/5.14/4.95(3xd, J=9/5.4/10.2Hz, H-29/26/20); 4.28(dxd,         J=4.5/13.7Hz,         H-6equ.); 3.64/3.58/3.41/3.32(4xOCH.sub.3).    104  5.28/5.06/4.87(3xd, J=8.9/7.2/10.4Hz, H-29/26/20); 4.22(db,         J=13.5Hz,         H-6equ.); 3.33/3.42/3.56(3xs, 3xOCH.sub.3).    105  6.44/7.82(2xsb, 2xNH); 5.22(sb, H-26); 5.15(d, J=8.9Hz, H-29);         4.95(d,         J=9.2Hz, H-20); 4.53(sb, H-6equ.); 4.18(dxd, J=4.6/13.5Hz, H-24);         3.25(q,         H-21); 3.15(dxt, H-6a); 3.39/3.42/3.435(3xs, 3xOCH.sub.3);    106  5.26/5.08/4.88(3xd, J=9.5/6.9/10.4Hz, H-29/26/20); 4.24(dxd,         J=4.4/13.5Hz,         H-6equ.); 4.03(tb, H-24); 3.56/3.41/3.33(3xs, 3xOCH.sub.3);         2.97/2.76(2xs,         2xNCH.sub.3).    107.sup.5)         5.32/5.13/4.97/3xd, H-26/29/20); 3.95(m, H-24); 3.36/3.39/3.42(3xs,         3xOCH.sub.3.    117  5.25/5.05(2xd, H-26/29); 3.31/3.36/3.42(3xs, 3xOCH.sub.3); 3.03(m,         H-32).    118.sup.6)         5.2/5.02(m/d, H-29/26/20); 4.38(dxd, H-6equ.); 3.42/3.38/3.35(3xs,         3xOCH.sub.3).    __________________________________________________________________________

    __________________________________________________________________________    .sup.13 C-NMR-Spectra    (CDCl.sub.3)    Example:         spectrum:    __________________________________________________________________________    6f   212.32(C-22), 202.22(C-10), 170.27(C-8), 165.04(C-1), 139.26(C-19),         3.22(C-29), 130.93(C-28); 123.57(C-20); 84.466/84.145(C-26/32),         78.475(C-13), 77.588(C-15), 76.573(C-10), 73.478/73.451(C-33/14),         72.14(C-2), 66.9(C-24), 58.816/57.042/56.483(3xOCH.sub.3),         54.493(C-21),         46.995(C-18), 45.819(C-23).    7d   210.5/202.5/170.9/165.4/75.2(C-22/10/8/1/9).    7e, 79         210.1/205.8/172.8/165.9/18.2(C-22/10/8/1/9).    9a   170.12/169.72(C-1/8), 150.4(O.CO.O), 138.67(C-19), 132.47(C-28),         129.62(C-29), 123.35(C-20), 96.79(C-9), 83.997(C-32).    9c   201.70(C-9), 170.14/165.05(C-1/8), 149(O.CO.O), 138.01(C-19),         131.11         (C-29), 129.50(C-28), 124.25(C-20), 83.916(C-32).    16   199.10(C-10), 166.99/165.87(C-1/8), 152.3/149.22(O.CO.O), 138.28/         131.02/129.68/124.16(C-19/29/28/20), 84.126(OCMe.sub.3),         83.992(C-32),         80.535(C-9), 79.17(C-13), 78.237(C-24), 77.892(C-22), 77.524(C-15),         77.01(C-26), 73.671(C-14), 73.384(C-33), 72.137(C-2), 57.495/         56.934/56.551(3xOCH.sub.3), 49.047(C-18), 44.062(C-21),         38.118/37.531         C-25/C-6), 35.071/34.636/34.39(C-30/31/11), 32.647(C-16), 31.094/         30.797/30.584(C-34/3/35); 27.97(C-12), 27.58(C-17), 25.673(C-23),         24.65         C-36), 23.304(C-5), 21.875(17-methyl), 20.818(C-4),         17.362(19-methyl),         14.783(28-methyl), 13.223(11-methyl), 11.929(C-37);         9.26(25-methyl).    17   167.86/166.00(C-1/8), 152.41/149.72(2xO.CO.O), 137.22/133.09/128.98/         124.98(C-19/29/28/20), 104.10(C-9), 88.88(C-10), 57.326/56.963/56.226         3xOCH.sub.3),50.655(C-18), 46.017(C-25), 42.98(C-21), 39.997(C-6),         35.237         C-30), 35.026(C-16), 34.39(C-12), 33.991(C-31), 31.962(C-11),         31.287/31.250(C-23/34), 30.312(C-35), 26.284(C-3), 25.840(C-36),         25.383(C-17).    18   201.51(C-10), 170.89(C-1), 164.82(C-8), 150.03(O.CO.O), 137.85/         131.44/129.65/124.84(C-19/29/28/20).    23a  170.66/170.56(C-1/8), 149.86(O.CO.O), 138.30(C-19), 130.39(C-28),         129.80(C-29), 123.91(C-20), 84.226(C-32), 80.051(C-13), 79.23(C-9),         78.966/78.904(C-22/24).    23b  171.65/170.91(C-1/8), 149.44(O.CO.O), 138.44(C-19), 130.20(C-28),         129.36(C-29), 123.80(C-20), 84.138(C-32), 81.238(C-9), 80.48(C-13),         79.403(C-22), 79.111(C-10), 78.927(C-24), 77.25(C-14),         76.994(C-15),         75.947(C-26).    24b  172.97(C-1), 168.48(C-8), 134.4(C-19), 131.59(C-28), 128.97(C-29),         126.53(C-20), 84.166(C-32), 75.195(C-33), 58.033/56.829/56.127         (3xOCH.sub.3), 48.844(C-18), 46.212(C-21).    25   167.73/164.85(C-1/8), 149,69(O.CO.O), 136.79(C-19), 132.39(C-28),         132.39/130.73(C-28/29), 128.53(C-20), 84.111(C-32), 57.693/56.820/         56.472(3xOCH.sub.3).    26a  202.42(C-9), 171.13(C-1), 165.28(C-8), 136.11(C-19), 132.62(C-29),         131.12(C-28), 126.82(C-20), 84.113(C-32), 58.456(OCH.sub.3), 56.531         (2xOCH.sub.3), 49.714(C-18), 46.373(C-23-).    26b  173.74(C-1), 168.91(C-8), 137.50(C-19), 131.73(C-29), 128.58(C-28),         26.33(C-20), 84.208(C-32), 57.2/57.061/56.676(3xOCH.sub.3).    28   201.2(C-10); 168.6(C-1); 165.6(C-8); 137.4(C-19); 130.9(C-28);         128.9(0-20);         128.5(C-29).    8    209.9/208.9/199.45/165.4/163.1(C-22/14/10/1/8)         159.04(-OCHO).    42   208.54(C-22), 199.53(C-10), 166.42(C-1), 164.38(C-8), 158.58(OCHO),         140.28(C-19), 137.73(C-29), 130.79(C-28), 123.57(C-20),         66.243(C-26),         84.057(C-32), 76.9(C-14), 75.069(C-33), 73.417(C-2).    46   209.27(C-22), 199.20(C-10), 167.64/163.74(C-1/8), 154.47(O.CO.N),         140.50/137.89/130.14/123.39(C-19/29/28/20), 70.206(C-2).    47a  210.32(C-22), 167.78/167.16(C-1/8), 155.54(O.CO.N), 138.79(C-19),         135         (b, C-29); 131.02(C-28), 124.43(C-20), 91.609(C-10), 84.054(C-32),         75.092(C-33), 68.584(C-24), 58.109/58.042/57.942(3xOCH.sub.3).    47b  208.65/200.42(C-22/14), 167.39/164.83(C-1/8), 154.24(O.CO.N),         139.33         (C-19), 137.29(C-29), 130.71(C-28), 124.16(C-20).    48   209.25(C-22), 169.24(C-1), 166.27(C-8), 153.41(O.CO.N),         140.69(C-19),         140.29(C-29), 129.40(C-28), 122.82(C-20), 87.968(C-26),         90.905/86.991         (C-9/10), 84.261(C-32), 61.503(15-OCH.sub.3), 58.071(32-OCH.sub.3),         56.677         (13-OCH.sub.3).    49   209.14(C-22), 184.68(O.CS.N), 168.92(C-1), 165.28(C-8),         141.03(C-19),         139.72(C-29), 129.43(C-28), 122.65(C-20), 95.02(C-10), 91.581(C-9),         88.676(C-26), 84.297(C-32), 82.275(C-13), 78.245(C-15),         75.575/75.432         (C-33114), 72.818(C-2), 68.016(C-24), 61.514(15-OCH.sub.3), 58.238         (32-OCH.sub.3), 56.806(13-OCH.sub.3), 56.512(C-21), 48.776(C-23),         30.083(N-me-         thyl).    53   210.10/208.92/206.25(C-22/10/14), 167.39/164.05(C-1/8),         139.39/138.10/         130.36/123.85(C-19/29/28/20), 81.232(C-9), 80.082(C-15).    54   209.31/208.70/204.01(C-22/10/14), 167.92/163.88(C-1/8),         139.79/137.45/         130.83/123.97(C-19/29/28120), 83.118(C-10), 67.831(C-24), 58.512/         58.027/58.02/54.311(4xOCH.sub.3).    55   208.92(C-22), 198.98(C-10), 166.97/163.29(C-1/8), 140.66/137.29/         131.02/123.46(C-19/29/28/20).    56   208.89(C-22), 199.66(C-10), 165.85/164.51(C-1/8), 139.92/137.41/         130.13/123.35(C-20/29/28/20), 70.59(C-2), 67.291(C-24),         62.863(C-9).    57   209.55(C-22), 196.68(C-10), 166.0/164.38(C-1/8), 140.28/137.05/130.88         /         123.28(C-19/29/28120), 85.703(C-26), 84.097(C-32), 75.189(C-33),         70.389(C-2), 68.139(C-24), 62.075(C-9), 60.122/58.019/57.752(3xOCH.su         b.3),         56.213(C-21), 48.031(C-23), 46.862(C-18), 16.043(19-methyl), 11.14         (28-methyl).    59   208.58(C-22), 203.72(C-10), 170.7(C-1), 163.86(C-8), 140.39/137.51/         130.96/123.69(C-19/29/28/20), 86.028(C-26), 84.051(C-32), 80.267         (C-15), 79.691(C-13), 76.424(C-9), 75.118(C-33), 73.368(C-14),         72.925         (C-2), 68.033(C-24), 61.289/57.928/55.55(3xOCH.sub.3), 56.357(C-21),         47.658         (C-18), 47.291(C-23).    66   209.5/204.6/167.5/164.3/81.5(C-22/10/1/8/9).    69b  209.62(C-22), 204.50(C-10), 169.09/164.71(C-1/8), 140.61/135.79/130.8         /         123.44(C-19/29/28/20), 77.56(C-9), 71.403(C-2).    108  211.33(C-22), 199.36(C-10), 166.71/164.47(C-1/8), 139.03/133.59/         130.73/124.90(C-19/29/28/20), 85.405(C-26), 84.14(C-32),         78.99(C-13),         77.963(C-15), 75.699(C-14), 73.466(C-33), 72.245(C-2),         67.223(C-24),         64.425(C-9), 57.521/56.865/56.522(3xOCH.sub.3), 55.062(C-21),         9.094(25-me-         thyl).    109  211.8/1197.45(C-22/10), 165.0/164.76(C-1/8), 138.26/131.68/130.93/         123.37(C-19/29/28/20), 62.723(C-9), 9.371(25-methyl).    110  210.07/209.53/205.85(C-22/14/10), 167.32/164.52(C-1/8),         139.69/135.58/         130.53/123.81(C-19/29/28/20), 81.337(C-9), 72.293(C-2), 8.58(25-me-         thyl).    111  211.371206.86/203.55(C-22,/14/10), 167.76/164.71(C-1/8),         138.96/134.31/         130.30/124.64(C-19/29128/20).    112  200.24(C-10), 167.81/166.31(C-118), 149.01(O.CO.O), 138.54/129.73/         129.13/123.57(C-19/29/28/20), 74.637(C-9), 11.737(C-37), 10.257         (25-methyl).    113  201.74(C-10), 170.16/165.04(C-1/8), 149.25(O.CO.O), 76.213(C-9),    114.sup.6)         173.26/168.76(C-8/1), 138.44/131.93/129.13/126.4(C-19/29/28/20),         84.242         (C-32), 79.984/79.887/79.744(C-10/26/9), 72.737(C-2).    116  213.24(C-22), 168.09/166.97(C-1/8), 155.52(O.CO.N), 137.69/131.32/         130.45/123.89(C-19/29/28/20), 8.891(25-methyl)    __________________________________________________________________________     .sup.1) 250 MHz/CD.sub.3 OD     .sup.2) 250 MHz/CDCl.sub.3     .sup.3) 500 MHz/CDCl.sub.3 + CD.sub.3 OD     .sup.4) 330+ K.     .sup.5) 323° K.     .sup.6) 320° K.     .sup.7) 250 MHz

The compounds of the invention in free form or pharmaceuticallyacceptable salt form, hereinafter briefly named the "agents of theinvention", possess pharmacological activity. They are thus useful aspharmaceuticals. In particular they possess antiinflammatory, andimmunosuppressant and antiproliferative activity.

The antiinflammatory activity may e.g. be determined in the followingtest methods, wherein abbreviations have the following significance:

DNP=2,4-dinitrophenol

DNFB=2,4-dinitrofluorobenzene

TPA=12-0-tetradecanoylphorbol-13-acetate

1. Inhibition of mast cell degranulation in vitro

Murine mast cells (CFTL-12) are treated with DNP-specific IgE overnight.Degranulation is triggered by the addition of antigen (DNP) and measuredas hexosaminidase activity in cell supernatant after 60 minutes in acolorimetric assay. Inhibitory substances are added 30 minutes prior toDNP.

The agents of the invention elicit in this test degranulation of mastcells (IC₅₀) at a dosage from about 1 ng/ml to about 50 ng/ml.

2. Oxazolone-induced allergic contact dermatitis (mouse)

the test method is as described in F. M. Dietrich and R. Hess, Int.Arch. Allergy 38 (1970) 246-259!:

The agents of the invention elicit in this test an activity (inhibitionof inflammatory swelling) of up to 58% upon a single topical applicationas a 0.01% solution. Hydrocortisone (1.2%) is inactive under theseconditions in this model and indomethazine (3.6%) inhibits inflammationby only 22%.

3. DNFB-induced allergic contact dermatitis

(the test method is as described in e.g. EP 315 978):

Two topical applications of a 0.13% formulation of the agents of theinvention result in inhibition of the inflammatory reaction by up to44%.

4. Inhibition of phorbol ester (TPA)--induced irritant contactdermatitis (mouse)

(the test method is as described in e.g. EP 315 978):

The agents of the invention elicit in this test upon single applicationof a 0.4-3.6% formulation an inhibition of the inflammatory reaction byup to 40%.

5. Inhibition of arachidonic acid--induced irritant contact dermatitis(mouse)

Female NMRI mice are treated topically on both the inner and outer sidesof the right ear with 10 μl of DAE 244 (DMSO/acetone/ethanol=2/4/4)containing the test compound (usually 1.2 and 3.6%). After 30 minutesthe right ear is treated topically with 10 μl (both inside and out) ofacetone containing 1 mg of arachidonic acid. After a further 90 minutesthe mice are sacrificed and the ears cut off at the cartilage line andweighed. The difference in weight between left and right ears iscalculated and the % inhibition taken relative to the group treated witharachidonic acid alone.

The agents of the invention elicit in this test upon single applicationof a 0.4-3.6% formulation an inhibition of the inflammatory reaction byup to 30%.

6. Inhibition of ionophore (A 23187)--induced irritant contactdermatitis (mouse)

Female NMRI mice are treated topically on the inside of the right earwith 15 μl of acetone/10% DMSO containing 15 μg of A 23187 with orwithout the test compound (usually 0.4% and 1.2%). After 7.5 h the miceare sacrificed and the ears cut off at the cartilage line and weighed.The difference between the left and right ears is calculated for eachmouse and the % inhibition is taken relative to the group havingreceived A 23187 alone.

The agents of the invention elicit in this test upon single applicationof a 0.4-1.2% formulation an inhibition of the inflammatory reaction byup to 72%. Indomethazine used for comparison inhibited inflammation by44% at 1.2% concentration.

Immunosuppressant and antiproliferative activity may e.g. be determinedin the following test methods:

7. Proliferative response of lymphocytes to allogen stimulation in themixed lymphocyte reaction (MLR) in vitro

the test method is as described in e.g. T. Meo, "The MLR in the Mouse",Immunological Methods, L. Lefkovits and B. Pernis, Eds., Academic Press,N.Y. (1979) 227-239!:

The agents of the invention elicit in this test suppression of mixedlymphocytes (IC₅₀) at a dosage of from about 10 ng/ml to about 100ng/ml.

8. Inhibition of the primary humoral immune response to sheeperythrocytes in vitro

the test method is as described in R. I. Mishell and R. W. Dutton,Science 153 (1966) 1004-1006; R. I. Mishell and R. W. Dutton, J. Exp.Med. 126 (1967) 423-442!:

The agents of the invention are active in this test with an IC₅₀ of fromabout 0.0024 μg/ml to about 0.32 μg/ml.

9. Inhibition of proliferation of human keratinocytes

(the test method is as described in e.g. EP 539326):

The agents of the invention are active in this test at concentrations offrom about 3 μM/ml to about 10 μM/ml, resulting in an inhibition of fromabout 20% to about 50%.

10. Inhibition of phorbol ester (TPA)--induced epidermalhyperproliferation (mouse)

For induction of epidermal hyperproliferation TPA (0.005%) is applied tothe pinna surface on days 1 and 3. The test compound is applied to thesame sites once daily on days 1, 2, 3 and 4. The vehicle is applied inthe same way to TPA-treated control animals. Evaluation ofantiproliferative activity of the test compound is performed on day 4, 6hours after the last application, by immunohistological examination ofthe incidence of BrdU-staining keratinocytes (BrdU injected one hourbefore the animals are sacrificed labels cells at the S-phase) and bymeasurement of the epidermal area per section area in test and controlanimals.

The agents of the invention elicit in this test upon 4 applications of a0.4-1.2% formulation an inhibition of BrdU-labeling by 60-70% and aninhibition of epidermal hyperplasia by 17-42%.

The agent of Examples 71 (and 6d) and the agent of Example 93,particularly the agent of Example 71 (6d) are the preferred agents forthe above indications. It has for example been determined that in theabove test 6. these agents in the form of a 1.2% preparation have betteractivity than a corresponding 1.2% preparation of indomethazine. It is,therefore, indicated that for the above uses the compounds of Examples71 (6d) and 93 may be administered to larger meals, for example humans,by similar modes of administration at similar or lower dosages thanconventionally employed with indomethazine.

The agents of the invention are therefore useful as antiinflammatoryagents and as immunosuppressant and antiproliferative agents for topicaland systemic use in the prevention and treatment of inflammatory andhyperproliferative conditions and of conditions requiringimmunosuppression, such as

a) treatment of inflammatory and hyperproliferative skin diseases, suchas atopical dermatitis, contact dermatitis and further eczematousdermatoses, seborrhoeic dermatitis, Lichen planus, Pemphigus, bullousPemphigoid, Epidermolysis bullosa, vasculitides, erythemas, cutaneouseosinophilias, Lupus erythematosus, acne, psoriasis and cutaneoustumors;

b) prevention and treatment of allergic diseases such as extrinsicasthma, rhinitis, conjunctivitis, atopic eczema, urticaria/angioedema,food/drug allergy and anaphylaxis;

c) prevention and treatment of

resistance in situations of organ or tissue transplantation, e.g. ofheart, kidney, liver, bone marrow and skin,

graft-versus-host disease, such as following bone marrow grafts,

autoimmune diseases such as rheumatoid arthritis, systemic Lupuserythematosus, Hashimoto's thyroiditis, multiple sclerosis, Myastheniagravis, diabetes type I and uveitis,

skin manifestations of immunologically-mediated disorders; and

alopecia areata.

The agents may be administered systemically or topically. For the aboveindications the appropriate dosage will, of course, vary depending upon,for example, the host, the mode of administration and the nature andseverity of the condition being treated. However, in general, beneficialresults are indicated to be obtained systemically at daily dosages offrom about 1.0 mg/kg to about 10 mg/kg animal body weight. An indicateddaily dosage in the larger mammal is in the range of from about 10 mg toabout 1000 mg, conveniently administered, for example, in divided dosesup to four times a day or in retard form. For topical use beneficialresults are obtained upon local administration at a concentration offrom about 1% to about 3% of active substance several times daily, e.g.2 to 5 times daily.

The agents of the invention may be administered by any conventionalroute, in particular enterally, e.g. orally, e.g. in the form of tabletsor capsules, or topically, e.g. in the form of lotions, gels, creams,sprays, and solutions such as ophthalmic or nasal solutions or aerosolsfor local treatment of skin and mucosal membranes, e.g. the eye,respiratory tract, vagina, oral and nasal cavity.

Pharmaceutical compositions e.g. for topical application comprising anagent of the invention in association with a least one pharmaceuticallyacceptable carrier or diluent may be manufactured in conventional mannerby mixing with a pharmaceutically acceptable carrier or diluent. Unitdosage forms contain, for example, from about 0.0025 mg to about 50 mgof active substance.

Topical administration is e.g. to the skin. A further form of topicaladministration is to the eye, e.g. for the treatment of immune-mediatedconditions of the eye, such as: autoimmune diseases, e.g. uveitis,keratoplasy and chronic keratitis; allergic conditions, e.g. vernalconjunctivitis; inflammatory conditions and corneal transplants, by thetopical administration to the eye surface of an agent of the inventionin a pharmaceutically acceptable ophthalmic vehicle.

The ophthalmic vehicle is such that the compound is maintained incontact with the ocular surface for a sufficient time period to allowthe compound to penetrate the corneal and internal regions of the eye,e.g. the anterior chamber, posterior chamber, vitreous body, aqueoushumor, vitreous humor, cornea, iris/ciliary, lens, choroid/retina andsclera. The pharmaceutically acceptable ophthalmic vehicle may be e.g.an ointment, a vegetable oil or an encapsulating material.

Whilst the antiinflammatory and immunosuppressant and antiproliferativeactivity is the main activity of the agents of the invention they alsopossess some degree of activity in increasing sensitivity to, or inincreasing the efficacy of, chemotherapeutic drug therapy. This activitymay e.g. be determined according to the test methods described in EP 360760.

The compounds of the invention are therefore useful in reversingchemotherapeutic drug resistance of varying types, e.g. acquired orinnate, or in increasing sensitivity to administered drug therapy, e.g.as a means of reducing regular chemotherapeutic dosage levels, forexample in the case of anti-neoplastic or cytostatic drug therapy, as ameans of decreasing overall drug toxicity and, more especially, as ameans of reversing or reducing resistance, including both inherent andacquired resistance, to chemotherapy.

The invention thus also concerns the use of an agent of the invention asa pharmaceutical, particularly as an antiinflammatory, and as animmunosuppressant and antiproliferative agent; it further provides apharmaceutical composition comprising an agent of the invention inassociation with at least one pharmaceutical carrier or diluent. Itfurther provides a method of treatment of inflammatory andhyperproliferative conditions and of conditions requiringinmmunosuppression which comprises administering a therapeuticallyeffective amount of an agent of the invention to a patient in need ofsuch treatment.

I claim:
 1. A compound of formulae I to III ##STR11## wherein the symbol₋₋ -- -- represents a single bond or, when R_(2a) is absent, a doublebond;R₁ represents an optionally protected hydroxy group and R_(1a)represents hydrogen;or R₁ and R_(1a) together represent oxo; R₂represents an optionally protected hydroxy group or together with R₄forms the --OC(═O)O-- group, and R_(2a) represents hydrogen or isabsent;whereby when the symbol ₋₋ -- -- is a single bond, R₂ togetherwith R_(2a) also represents oxo; R₃ represents methyl, ethyl, n-propylor allyl; R₄ represents optionally protected hydroxy or together with R₂forms the --OC(═O)O-- group, and R_(4a) represents hydrogen;or R₄together with R_(4a) represents oxo; R₅ represents alkoxycarbonyloxy,halogen, optionally protected hydroxy, lower alkoxy, acyloxy or a group--OC(═X)N(R₁₀)R₁₁ ;or R₅ together with R_(6a) forms a group--OC(═X)N(R'₁₀)-- attached with the nitrogen atom to the carbon atomcarrying R_(6a), whereby X represents oxygen or sulfur, R₁₀ and R₁₁independently represent hydrogen or lower alkyl or together with thenitrogen atom form a five- or six-membered ring optionally containing asecond heteroatom such as nitrogen or oxygen, and R'₁₀ is hydrogen orlower alkyl; or R₅ together with R_(8a) represents oxy, whereby R₈represents hydroxy; R₆ represents hydroxy, and R_(6a) representshydrogen or together with R₅ forms a group --OC(═X)N(R'₁₀)-- as definedabove;or R₆ and R_(6a) together represent oxo; R'₅ represents optionallyprotected hydroxy, lower alkoxy or acyloxy andR'₆ represents hydroxy; orR'₅ and R'₆ together form the --OC(═O)O-- group; R"₅ represents hydroxyor lower alkoxy and R"₆ represents hydroxy;or R"₅ and R"₆ together formthe --OC(═O)O-- group; R₇ represents methoxy or hydroxy; R₈ representsan optionally protected hydroxy group, acyloxy, imidazolylcarbonyloxy oralkoxycarbonyloxy and R_(8a) represents hydrogen;or R₈ representshydroxy and R_(8a) together with R₅ represents oxy; or R₈ together withR_(8a) represents oxo; and n represents 1 or 2; in free form or saltform.
 2. A compound according to claim 1 of formulae I to III as definedin claim 1, with the proviso thatR₂ and R₄ are other than together the--OC(═O)O-- group; R₄ is other than protected hydroxy; R₅ is other thanalkoxycarbonyloxy, halogen, protected hydroxy, a group--OC(═X)N(R₁₀)R₁₁or together with R_(6a) a group --OC(═X)N(R'₁₀)-- above; R'₅ is otherthan protected hydroxy; and R₈ is other than protected hydroxy oralkoxycarbonyloxy of altogether more than 2 carbon atoms, in free formor salt form.
 3. A compound according to claim 1 of formulae I to III asdefined in claim 1, with the proviso that R₄, R₅ and R'₅ are other thanprotected hydroxy, and R₈ is other than alkoxycarbonyloxy of altogethermore than 2 carbon atoms, in free form or salt form.
 4. A compound offormulae 1, II, or III ##STR12## wherein the symbol ₋₋ -- -- representsa single bond or, when R_(2a) is absent a double bond;R₁ representshydroxy or hydroxy protected by tert-butoxycarbonyl,tri(C₁₋₄)alkylsilyl, or methylsulphonyl and R_(1a) representshydrogen;or R₁ and R₁ together represent oxo; R₂ represents hydroxy orhydroxy protected by tert-butoxycarbonyl, tri(C₁₋₄)alkylsilyl, ormethylsulphonyl or together with R₄ forms the --OC(═O)O-- group, andR_(2a) represents hydrogen or is absent; and when the symbol ₋₋ -- -- isa single bond, R₂ together with R_(2a) also represents oxo; R₃represents methyl, ethyl, n-propyl or allyl; R₄ represents hydroxy orhydroxy protected by tert-butoxycarbonyl, tri(C₁₋₄)alkylsilyl, ormethylsulphonyl or together with R₂ forms the --OC(═O)O-- group, andR_(4a) represents hydrogen; or R₄ together with R_(4a) represents oxo;R₅ represents (C₁₋₄)alkoxycarbonyloxy, halogen, hydroxy or hydroxyprotected by tri (C₁₋₄) alkylsilyl or methylsulphonyl, (C₁₋₄)alkoxy,(C₁₋₄)alkylcarbonyloxy, formyloxy, benzyloxy or a group--OC(═X)N(R₁₀)R₁₁ ; or R₅ together with R_(6a) forms a group--OC(═X)N(R'₁₀)-- attached with the nitrogen atom to the carbon atomcarrying R_(6a') wherein X represents oxygen or sulfur R₁₀ and R₁₁independently represent hydrogen or (C₁₋₄)alkyl or together with thenitrogen atom form 4-morpholinyl; R'10 represents hydrogen or(C₁₋₄)alkyl; or R₅ together with R_(8a) represents oxy and R₈ representshydroxy; R₆ represents hydroxy, and R_(6a) represents hydrogen ortogether with R₅ forms a group --OC(═X)N(R'₁₀)-- as defined above; or R₆and R_(6a) together represent oxo; R'₅ represents hydroxy or hydroxyprotected by tert-butoxycarbonyl, tri(C₁₋₄)alkylsilyl, ormethylsulphonyl, (C₁₋₄)alkoxy or (C₁₋₄)alkylcarbonyloxy, formyloxy,benzyloxy and R'₆ represents hydroxy; or R'₅ and R'₆ together form the--OC(═O)O-- group; R"₅ represents hydroxy or (C₁₋₄) alkoxy and R"₆represents hydroxy; or R"₅ and R"₆ together form the --OC(═O)O-- group;R₇ represents methoxy or hydroxy; R₈ represents hydroxy or hydroxyprotected by tri (C₁₋₄) alkylsilyl or methylsulphonyl,(C₁₋₄)alkylcarbonyloxy, formyloxy, benzyloxy, imidazolylcarbonyloxy or(C₁₋₄) alkoxycarbonyloxy and R_(8a) represents hydrogen; or R₈represents hydroxy and R_(8a) together with R₅ represents oxy; or R₈together with R_(8a) represents oxo; and n represents 1 or 2;in freeform.
 5. A compound according to claim 4 of formulae Iq to IIIq##STR13## wherein R_(1q) represents hydroxy optionally protected bytert-butyldimethylsilyl or methylsulfonyl and R_(1aq) representshydrogen;or R_(1q) and R_(1aq) together represent oxo; R_(2q) representshydroxy optionally protected by tert-butyldimethylsilyl or together withR_(4q) forms the --OC(═O)O-- group; R_(3q) represents ethyl or allyl;R_(4q) represents hydroxy optionally protected bytert-butyldimethylsilyl or together with R₂ q forms the --OC(═O)O--group, andR_(4aq) represents hydrogen; or R_(4q) together with R_(4aq)represents oxo; R_(5q) represents methoxycarbonyloxy; chlorine; hydroxyoptionally protected by tert-butyldimethylsilyl, tert-butoxycarbonyl ormethylsulfonyl; methoxy; formyloxy, acetoxy or benzoyloxy; or a group--OC(═O)N(R_(10q))R_(11q) whereinR_(10q) and R_(11q) independentlyrepresent hydrogen or methyl or together with the nitrogen atom form4-morpholinyl; or R_(5q) together with R_(6aq) forms a group--OC(═X)N(R'_(10q))-- and R'_(10q) is hydrogen or methyl; or R_(5q)together with R_(8aq) represents oxy, whereby R_(8q) represents hydroxy;R_(6q) represents hydroxy, and R_(6aq) represents hydrogen or togetherwith R_(5q) forms a group --OC(═X)N(R'_(10q))--or R_(6q) and R_(6aq)together represent oxo; R'_(5q) represents hydroxy optionally protectedby benzoyl or acetyl andR'_(6q) represents hydroxy; or R'_(5q) andR'_(6q) together form the --OC(═O)O-- group; R"_(5q) represents hydroxyor methoxy and R"_(6q) represents hydroxy;or R"_(5q) and R"_(6q)together form the --OC(═O)O-- group; and R_(8q) represents hydroxyoptionally protected by tert-butyldimethylsilyl or methylsulfonyl;acetoxy or benzoyloxy; or 1-imidazolylcarbonyloxy; andR_(8aq) representshydrogen; or R_(8q) represents hydroxy and R_(8aq) together with R_(5q)represents oxy; or R_(8q) together with R_(8aq) represent oxo; in freeform.
 6. A compound according to claim 1 of formulae Is to IIIs##STR14## wherein the substituents are as defined in claim 1, in freeform or salt form.
 7. A compound according to claim 6 whereinwhen R₁ isother than oxo together with R_(1a), then R₁ is bound with theα-configuration to the carbon atom in 33 position; R₃ preferably isbound with the α-configuration to the carbon atom in 21 position; whenR₄ is other than oxo together with R_(4a), then R₄ is bound with theα-configuration to the carbon atom in 22 position; in free form or saltform.
 8. The compound of formula I according to claim 4 whereinR_(1a),R_(2a) and R_(8a) represent hydrogen; R₁, R₂, R₅ and R₈ representhydroxy; R₃ represents ethyl; R₄ and R_(4a) together, and R₆ and R_(6a)together, represent oxo; the symbol ₋₋ -- -- represents a single bond;R₇ represents methoxy; and n represents 2 diastereoisomer B.
 9. Thecompound of formula I according to claim 4 whereinR_(1a) and R_(2a)represent hydrogen; R₁, R₂ and R₅ represent hydroxy; R₃ representsethyl; R₄ and R_(4a) together, R₆ and R_(6a) together, and R₈ and R_(8a)together, represent oxo; the symbol ₋₋ -- -- represents a single bond;R₇ represents methoxy; and n represents 2 diastereoisomer A.
 10. Thecompound of formula I according to claim 4 whereinR_(1a) and R_(2a)represent hydrogen; R₁ and R₂ represent hydroxy; R₃ represents ethyl; R₄and R_(4a) together, and R₆ and R_(6a) together, represent oxo; R₅ andR_(8a) together represent oxy; R₈ represents hydroxy; the symbol ₋₋ ---- represents a single bond; R₇ represents methoxy; and n represents 2diastereoisomer A.
 11. A compound according to claim 1 of formulae I,II, or III wherein the symbol ₋₋ -- -- represents a single bond or, whenR_(2a) is absent, a double bond;R₁ represents hydroxy or hydroxyprotected by tert-butoxycarbonyl, tri(C₁₋₄) alkylsilyl, ormethylsulphonyl and R_(1a) represents hydrogen; or R₁ and R_(1a)together represent oxo;R₂ represents hydroxy or hydroxy protected bytert-butoxycarbonyl, tri(C₁₋₄)alkylsilyl, or methylsulphonyl and R_(2a)represents hydrogen or is absent; and when the symbol ₋₋ -- -- is asingle bond, R₂ together with R_(2a) also represents oxo; R₃ representsmethyl, ethyl, n-propyl or allyl; R₄ represents hydroxy, and R_(4a)represents hydrogen; or R₄ together with R_(4a) represents oxo; R₅represents hydroxy, (C₁₋₄)alkoxy, (C₁₋₄) alkylcarbonyloxy, formyloxy,benzyloxy or R₅ together with R₈ a represents oxy, and R₈ representshydroxy; R₆ represents hydroxy, and R_(6a) represents hydrogen; or R₆and R_(6a) together represent oxo; R'₅ represents hydroxy, (C₁₋₄)alkoxyor (C₁₋₄)alkylcarbonyloxy, formyloxy, benzyloxy and R'₆ representshydroxy; or R'₅ and R'₆ together form the --OC(═O)O-- group; R"₅represents hydroxy or (C₁₋₄)alkoxy and R"₆ represents hydroxy; or R"₅and R"₆ together form the --OC(═O)O-- group; R₇ represents methoxy orhydroxy; R₈ represents hydroxy, (C₁₋₄)alkylcarbonyloxy, formyloxy,benzyloxy imidazolylcarbonyloxy or methoxycarbonyloxy and R_(8a)represents hydrogen; or R₈ represents hydroxy and R_(8a) together withR₅ represents oxy; or R₈ together with R_(8a) represents oxo; and nrepresents 1 or 2;in free form.
 12. A compound according to claim 1 offormulae I, II, or III in free form.
 13. A compound according to claim 4of formulae I, II or III in free form.
 14. A pharmaceutical compositioncomprising a compound of formulae I, II or III as defined in claim 1 infree form or in pharmaceutically acceptable salt form in associationwith at least one pharmaceutically acceptable carrier or diluent.
 15. Amethod of treatment of inflammatory or hyperproliferative conditions orof conditions requiring immunosuppression which comprises administeringa therapeutically effective amount of a compound of formulae I, II, orIII as defined in claim 1 in free form or pharmaceutically acceptablesalt form to a patient in need of such treatment.